Soft classification and regression analysis of audiometric phenotypes of age-related hearing loss.

Age-related hearing loss has a complex etiology. Researchers have made efforts to classify relevant audiometric phenotypes, aiming to enhance medical interventions and improve hearing health. We leveraged existing pattern analyses of age-related hearing loss and implemented the phenotype classification via quadratic discriminant analysis (QDA). We herein propose a method for analyzing the exposure effects on the soft classification probabilities of the phenotypes via estimating equations. Under reasonable assumptions, the estimating equations are unbiased and lead to consistent estimators. The resulting estimator had good finite sample performances in simulation studies. As an illustrative example, we applied our proposed methods to assess the association between a dietary intake pattern, assessed as adherence scores for the dietary approaches to stop hypertension diet calculated using validated food-frequency questionnaires, and audiometric phenotypes (older-normal, metabolic, sensory, and metabolic plus sensory), determined based on data obtained in the Nurses' Health Study II Conservation of Hearing Study, the Audiology Assessment Arm. Our findings suggested that participants with a more healthful dietary pattern were less likely to develop the metabolic plus sensory phenotype of age-related hearing loss.

Metabolic and Sensory Components of Age-Related Hearing Loss: Associations With Distortion- and Reflection-Based Otoacoustic Emissions.

Age-related hearing loss is difficult to study in humans because multiple genetic and environmental risk factors may contribute to pathology and cochlear function declines in older adults. These pathologies, including degeneration of the stria vascularis, are hypothesized to affect outer hair cells responsible for active cochlear amplification of low-level sounds. Otoacoustic emission (OAE) measures are used to quantify the energy added to the traveling wave in cochlear amplification, which typically weakens with increased pure-tone thresholds and for older individuals. Thus, the current study evaluated two OAE measures for individuals with different components of age-related hearing loss. We examined two retrospective adult lifespan datasets (18 to 89+ years of age) from independent sites (Medical University of South Carolina and Boys Town National Research Hospital), which included demographics, noise history questionnaires, distortion-product otoacoustic emissions (DPOAE), and cochlear reflectance (CR). Metabolic and sensory estimates of age-related hearing loss were derived from the audiograms in each dataset, and then tested for associations with DPOAE and CR. The results showed that metabolic estimates increased for older participants and were associated with lower overall DPOAE and CR magnitudes across frequency (i.e., lower fitted intercepts). Sensory estimates were significantly higher for males, who reported more positive noise histories compared to females and were associated with steeper negative across-frequency slopes for DPOAEs. Although significant associations were observed between OAE configurations, DPOAEs appeared uniquely sensitive to metabolic estimates. The current findings suggest that distortion-based measures may provide greater sensitivity than reflection-based measures to the components of age-related hearing loss.

Accurate phenotypic classification and exome sequencing allow identification of novel genes and variants associated with adult-onset hearing loss.

Adult-onset progressive hearing loss is a common, complex disease with a strong genetic component. Although to date over 150 genes have been identified as contributing to human hearing loss, many more remain to be discovered, as does most of the underlying genetic diversity. Many different variants have been found to underlie adult-onset hearing loss, but they tend to be rare variants with a high impact upon the gene product. It is likely that combinations of more common, lower impact variants also play a role in the prevalence of the disease. Here we present our exome study of hearing loss in a cohort of 532 older adult volunteers with extensive phenotypic data, including 99 older adults with normal hearing, an important control set. Firstly, we carried out an outlier analysis to identify genes with a high variant load in older adults with hearing loss compared to those with normal hearing. Secondly, we used audiometric threshold data to identify individual variants which appear to contribute to different threshold values. We followed up these analyses in a second cohort. Using these approaches, we identified genes and variants linked to better hearing as well as those linked to worse hearing. These analyses identified some known deafness genes, demonstrating proof of principle of our approach. However, most of the candidate genes are novel associations with hearing loss. While the results support the suggestion that genes responsible for severe deafness may also be involved in milder hearing loss, they also suggest that there are many more genes involved in hearing which remain to be identified. Our candidate gene lists may provide useful starting points for improved diagnosis and drug development.

Evidence for conflict monitoring during speech recognition in noise.

During difficult tasks, conflict can benefit performance on a subsequent trial. One theory for such performance adjustments is that people monitor for conflict and reactively engage cognitive control. This hypothesis has been challenged because tasks that control for associative learning do not show such "cognitive control" effects. The current study experimentally controlled associative learning by presenting a novel stimulus on every trial of a picture-speech conflict task and found that performance adjustments still occur. Thirty-one healthy young adults listened to and repeated words presented in background noise while viewing pictures that were congruent or incongruent (i.e., phonological neighbors) with the word. Following conflict, participants had higher word recognition (+17% points) on incongruent but not congruent trials. This result was not attributable to posterror effects nor a speed-accuracy trade-off. An analysis of erroneous responses showed that participants made more phonologically related errors than nonrelated errors only on incongruent trials, demonstrating elevated phonological conflict when the picture was a neighbor of the target word. Additionally, postconflict improvements appear to be due to better resolution of phonological conflict in the mental lexicon rather than decreased attention to the picture or increased attention to the speech signal. Our findings provide new evidence for conflict monitoring and suggest that cognitive control helps resolve phonological conflict during speech recognition in noise.

Accurate phenotypic classification and exome sequencing allow identification of novel genes and variants associated with adult-onset hearing loss.

Adult-onset progressive hearing loss is a common, complex disease with a strong genetic component. Although to date over 150 genes have been identified as contributing to human hearing loss, many more remain to be discovered, as does most of the underlying genetic diversity. Many different variants have been found to underlie adult-onset hearing loss, but they tend to be rare variants with a high impact upon the gene product. It is likely that combinations of more common, lower impact variants also play a role in the prevalence of the disease. Here we present our exome study of hearing loss in a cohort of 532 older adult volunteers with extensive phenotypic data, including 99 older adults with normal hearing, an important control set. Firstly, we carried out an outlier analysis to identify genes with a high variant load in older adults with hearing loss compared to those with normal hearing. Secondly, we used audiometric threshold data to identify individual variants which appear to contribute to different threshold values. We followed up these analyses in a second cohort. Using these approaches, we identified genes and variants linked to better hearing as well as those linked to worse hearing. These analyses identified some known deafness genes, demonstrating proof of principle of our approach. However, most of the candidate genes are novel associations with hearing loss. While the results support the suggestion that genes responsible for severe deafness may also be involved in milder hearing loss, they also suggest that there are many more genes involved in hearing which remain to be identified. Our candidate gene lists may provide useful starting points for improved diagnosis and drug development.

Deep learning classification of reading disability with regional brain volume features.

Developmental reading disability is a prevalent and often enduring problem with varied mechanisms that contribute to its phenotypic heterogeneity. This mechanistic and phenotypic variation, as well as relatively modest sample sizes, may have limited the development of accurate neuroimaging-based classifiers for reading disability, including because of the large feature space of neuroimaging datasets. An unsupervised learning model was used to reduce deformation-based data to a lower-dimensional manifold and then supervised learning models were used to classify these latent representations in a dataset of 96 reading disability cases and 96 controls (mean age: 9.86 ± 1.56 years). A combined unsupervised autoencoder and supervised convolutional neural network approach provided an effective classification of cases and controls (accuracy: 77%; precision: 0.75; recall: 0.78). Brain regions that contributed to this classification accuracy were identified by adding noise to the voxel-level image data, which showed that reading disability classification accuracy was most influenced by the superior temporal sulcus, dorsal cingulate, and lateral occipital cortex. Regions that were most important for the accurate classification of controls included the supramarginal gyrus, orbitofrontal, and medial occipital cortex. The contribution of these regions reflected individual differences in reading-related abilities, such as non-word decoding or verbal comprehension. Together, the results demonstrate an optimal deep learning solution for classification using neuroimaging data. In contrast with standard mass-univariate test results, results from the deep learning model also provided evidence for regions that may be specifically affected in reading disability cases.

Probability Distributions for Associations Between Cognitive Screening and Pure-tone Thresholds in Older Adults.

OBJECTIVES: Lower general cognitive function is frequently reported in older adults with elevated pure-tone thresholds. Here, we examined reason(s) for this association, including whether this relationship is dependent on the frequency range or extent of hearing loss and cognitive screening performance. DESIGN: Linear regression was used to examine associations between better-ear pure-tone thresholds and Mini-Mental Status Exam (MMSE) performance in a cross-sectional sample of relatively healthy older adults (N = 508; 68% women, 60-89+ years; M age = 72). Quantile regression was also used to identify the ranges of 0.5 and 4.0 kHz thresholds and MMSE scores where these variables exhibited significant associations. RESULTS: MMSE scores and pure-tone thresholds exhibited small but significant associations, particularly for better-ear 0.5 kHz thresholds. This hearing threshold and cognitive screening association was present among participants with better hearing, including the oldest older adults. There was limited evidence for mediating health condition effects on this association. An item analysis of the MMSE revealed that the MMSE and pure-tone threshold associations were largely due to the delayed recall item of the MMSE. CONCLUSIONS: Together, the small effect results are consistent with the extant literature and suggest that there are multiple reasons for modest pure-tone threshold and cognitive screening performance associations.

Auditory Cortex Asymmetry Associations with Individual Differences in Language and Cognition.

A longstanding cerebral lateralization hypothesis predicts that disrupted development of typical leftward structural asymmetry of auditory cortex explains why children have problems learning to read. Small sample sizes and small effects, potential sex-specific effects, and associations that are limited to specific dimensions of language are thought to have contributed inconsistent results. The large ABCD study dataset (baseline visit: N = 11,859) was used to test the hypothesis of significant associations between surface area asymmetry of auditory cortex and receptive vocabulary performance across boys and girls, as well as an oral word reading effect that was specific to boys. The results provide modest support (Cohen's d effect sizes ≤ 0.10) for the cerebral lateralization hypothesis.

Dyslexia Data Consortium Repository: A Data Sharing and Delivery Platform for Research.

Specific learning disability of reading, or dyslexia, affects 5-17% of the population in the United States. Research on the neurobiology of dyslexia has included studies with relatively small sample sizes across research sites, thus limiting inference and the application of novel methods, such as deep learning. To address these issues and facilitate open science, we developed an online platform for data-sharing and advanced research programs to enhance opportunities for replication by providing researchers with secondary data that can be used in their research (https://www.dyslexiadata.org). This platform integrates a set of well-designed machine learning algorithms and tools to generate secondary datasets, such as cortical thickness, as well as regional brain volume metrics that have been consistently associated with dyslexia. Researchers can access shared data to address fundamental questions about dyslexia and development, replicate research findings, apply new methods, and educate the next generation of researchers. The overarching goal of this platform is to advance our understanding of a disorder that has significant academic, social, and economic impacts on children, their families, and society.

Cortical asymmetries at different spatial hierarchies relate to phonological processing ability.

The ability to map speech sounds to corresponding letters is critical for establishing proficient reading. People vary in this phonological processing ability, which has been hypothesized to result from variation in hemispheric asymmetries within brain regions that support language. A cerebral lateralization hypothesis predicts that more asymmetric brain structures facilitate the development of foundational reading skills like phonological processing. That is, structural asymmetries are predicted to linearly increase with ability. In contrast, a canalization hypothesis predicts that asymmetries constrain behavioral performance within a normal range. That is, structural asymmetries are predicted to quadratically relate to phonological processing, with average phonological processing occurring in people with the most asymmetric structures. These predictions were examined in relatively large samples of children (N = 424) and adults (N = 300), using a topological asymmetry analysis of T1-weighted brain images and a decoding measure of phonological processing. There was limited evidence of structural asymmetry and phonological decoding associations in classic language-related brain regions. However, and in modest support of the cerebral lateralization hypothesis, small to medium effect sizes were observed where phonological decoding accuracy increased with the magnitude of the largest structural asymmetry across left hemisphere cortical regions, but not right hemisphere cortical regions, for both the adult and pediatric samples. In support of the canalization hypothesis, small to medium effect sizes were observed where phonological decoding in the normal range was associated with increased asymmetries in specific cortical regions for both the adult and pediatric samples, which included performance monitoring and motor planning brain regions that contribute to oral and written language functions. Thus, the relevance of each hypothesis to phonological decoding may depend on the scale of brain organization.

Evidence for cortical adjustments to perceptual decision criteria during word recognition in noise.

Extensive increases in cingulo-opercular frontal activity are typically observed during speech recognition in noise tasks. This elevated activity has been linked to a word recognition benefit on the next trial, termed "adaptive control," but how this effect might be implemented has been unclear. The established link between perceptual decision making and cingulo-opercular function may provide an explanation for how those regions benefit subsequent word recognition. In this case, processes that support recognition such as raising or lowering the decision criteria for more accurate or faster recognition may be adjusted to optimize performance on the next trial. The current neuroimaging study tested the hypothesis that pre-stimulus cingulo-opercular activity reflects criterion adjustments that determine how much information to collect for word recognition on subsequent trials. Participants included middle-age and older adults (N = 30; age = 58.3 ± 8.8 years; m ± sd) with normal hearing or mild sensorineural hearing loss. During a sparse fMRI experiment, words were presented in multitalker babble at +3 dB or +10 dB signal-to-noise ratio (SNR), which participants were instructed to repeat aloud. Word recognition was significantly poorer with increasing participant age and lower SNR compared to higher SNR conditions. A perceptual decision-making model was used to characterize processing differences based on task response latency distributions. The model showed that significantly less sensory evidence was collected (i.e., lower criteria) for lower compared to higher SNR trials. Replicating earlier observations, pre-stimulus cingulo-opercular activity was significantly predictive of correct recognition on a subsequent trial. Individual differences showed that participants with higher criteria also benefitted the most from pre-stimulus activity. Moreover, trial-level criteria changes were significantly linked to higher versus lower pre-stimulus activity. These results suggest cingulo-opercular cortex contributes to criteria adjustments to optimize speech recognition task performance.

Metabolic and Sensory Components of Age-Related Hearing Loss.

Age-related hearing loss is a multifactorial condition with effects of aging and environmental exposures that contribute to cochlear pathologies. Metabolic hearing loss involves declines in the endocochlear potential, which broadly reduce cochlear amplification of low-level sounds. Sensory hearing loss involves damage to outer hair cells that may eliminate amplification, especially for high-frequency sounds. A novel approach was developed to estimate the extent of metabolic and sensory components (in dB) for an individual, by combining hearing loss profiles to optimally approximate their hearing thresholds (audiogram). This approach was validated using estimates of metabolic and sensory hearing loss from retrospective datasets including gerbils, cross-sectional and longitudinal audiograms from older adults, a measure of speech recognition in noise, and histopathology case reports. Simulation results showed that well-approximated audiograms can produce accurate metabolic and sensory estimates. Estimates of metabolic and sensory components of age-related hearing loss differentiated gerbils with known strial and/or sensory pathologies based on age and exposures. For older adults, metabolic estimates consistently increased with age and were associated with poorer speech recognition in noise, while sensory estimates were related to sex and noise exposure differences. Histopathology case reports (with audiograms) that described strial and outer hair cell pathology in temporal bones from older donors showed significant differences in metabolic and sensory estimates, respectively. The results support the view that audiograms include information that can be used to estimate the metabolic and sensory components of age-related hearing loss.

Unique patterns of hearing loss and cognition in older adults' neural responses to cues for speech recognition difficulty.

Older adults with hearing loss experience significant difficulties understanding speech in noise, perhaps due in part to limited benefit from supporting executive functions that enable the use of environmental cues signaling changes in listening conditions. Here we examined the degree to which 41 older adults (60.56-86.25 years) exhibited cortical responses to informative listening difficulty cues that communicated the listening difficulty for each trial compared to neutral cues that were uninformative of listening difficulty. Word recognition was significantly higher for informative compared to uninformative cues in a + 10 dB signal-to-noise ratio (SNR) condition, and response latencies were significantly shorter for informative cues in the + 10 dB SNR and the more-challenging + 2 dB SNR conditions. Informative cues were associated with elevated blood oxygenation level-dependent contrast in visual and parietal cortex. A cue-SNR interaction effect was observed in the cingulo-opercular (CO) network, such that activity only differed between SNR conditions when an informative cue was presented. That is, participants used the informative cues to prepare for changes in listening difficulty from one trial to the next. This cue-SNR interaction effect was driven by older adults with more low-frequency hearing loss and was not observed for those with more high-frequency hearing loss, poorer set-shifting task performance, and lower frontal operculum gray matter volume. These results suggest that proactive strategies for engaging CO adaptive control may be important for older adults with high-frequency hearing loss to optimize speech recognition in changing and challenging listening conditions.

Translational and interdisciplinary insights into presbyacusis: A multidimensional disease.

There are multiple etiologies and phenotypes of age-related hearing loss or presbyacusis. In this review we summarize findings from animal and human studies of presbyacusis, including those that provide the theoretical framework for distinct metabolic, sensory, and neural presbyacusis phenotypes. A key finding in quiet-aged animals is a decline in the endocochlear potential (EP) that results in elevated pure-tone thresholds across frequencies with greater losses at higher frequencies. In contrast, sensory presbyacusis appears to derive, in part, from acute and cumulative effects on hair cells of a lifetime of environmental exposures (e.g., noise), which often result in pronounced high frequency hearing loss. These patterns of hearing loss in animals are recognizable in the human audiogram and can be classified into metabolic and sensory presbyacusis phenotypes, as well as a mixed metabolic+sensory phenotype. However, the audiogram does not fully characterize age-related changes in auditory function. Along with the effects of peripheral auditory system declines on the auditory nerve, primary degeneration in the spiral ganglion also appears to contribute to central auditory system aging. These inner ear alterations often correlate with structural and functional changes throughout the central nervous system and may explain suprathreshold speech communication difficulties in older adults with hearing loss. Throughout this review we highlight potential methods and research directions, with the goal of advancing our understanding, prevention, diagnosis, and treatment of presbyacusis.

Fully synthetic neuroimaging data for replication and exploration.

Scientific transparency, data exploration, and education are advanced through data sharing. However, risk for disclosure of personal information and institutional data sharing regulations can impede human subject/patient data sharing and thus limit open science initiatives. Sharing fully synthetic data is an alternative when it is not possible to share real or observed data. Here we describe a data sharing approach that borrows principles and methods from multiple imputation to replace observed values with synthetic values, thereby creating a fully synthetic neuroimaging dataset that accurately represents the covariance structure of the observed dataset. Predictor tables composed of demographic, site, behavioral and total intracranial volume (ICV) variables from 264 pediatric cases were used to create synthetic predictor tables, which were then used to synthesize gray matter images derived from T1-weighted data. The synthetic predictor tables demonstrated pooled variance and statistical estimates that closely approximated the observed data, as reflected in measures of efficiency and statistical bias. Similarly, the synthetic gray matter data accurately represented the variance and voxel-level associations with predictor variables (age, sex, verbal IQ, and ICV). The magnitude and spatial distribution of gray matter effects in the observed imaging data were replicated in the pooled results from the synthetic datasets. This approach for generating fully synthetic neuroimaging data has widespread potential for data sharing, including replication, new discovery, and education. Fully synthetic neuroimaging datasets can enable data-sharing because it accurately represents patterns of variance in the original data, while diminishing the risk of privacy disclosures that can accompany neuroimaging data sharing.

The Topology of Pediatric Structural Asymmetries in Language-Related Cortex.

Structural asymmetries in language-related brain regions have long been hypothesized to underlie hemispheric language laterality and variability in language functions. These structural asymmetries have been examined using voxel-level, gross volumetric, and surface area measures of gray matter and white matter. Here we used deformation-based and persistent homology approaches to characterize the three-dimensional topology of brain structure asymmetries within language-related areas that were defined in functional neuroimaging experiments. Persistence diagrams representing the range of values for each spatially unique structural asymmetry were collected within language-related regions of interest across 212 children (mean age (years) = 10.56, range 6.39-16.92; 39% female). These topological data exhibited both leftward and rightward asymmetries within the same language-related regions. Permutation testing demonstrated that age and sex effects were most consistent and pronounced in the superior temporal sulcus, where older children and males had more rightward asymmetries. While, consistent with previous findings, these associations exhibited small effect sizes that were observable because of the relatively large sample. In addition, the density of rightward asymmetry structures in nearly all language-related regions was consistently higher than the density of leftward asymmetric structures. These findings guide the prediction that the topological pattern of structural asymmetries in language-related regions underlies the organization of language.

Cingulo-opercular adaptive control for younger and older adults during a challenging gap detection task.

Cingulo-opercular activity is hypothesized to reflect an adaptive control function that optimizes task performance through adjustments in attention and behavior, and outcome monitoring. While auditory perceptual task performance appears to benefit from elevated activity in cingulo-opercular regions of frontal cortex before stimuli are presented, this association appears reduced for older adults compared to younger adults. However, adaptive control function may be limited by difficult task conditions for older adults. An fMRI study was used to characterize adaptive control differences while 15 younger (average age = 24 years) and 15 older adults (average age = 68 years) performed a gap detection in noise task designed to limit age-related differences. During the fMRI study, participants listened to a noise recording and indicated with a button-press whether it contained a gap. Stimuli were presented between sparse fMRI scans (TR = 8.6 s) and BOLD measurements were collected during separate listening and behavioral response intervals. Age-related performance differences were limited by presenting gaps in noise with durations calibrated at or above each participant's detection threshold. Cingulo-opercular BOLD increased significantly throughout listening and behavioral response intervals, relative to a resting baseline. Correct behavioral responses were significantly more likely on trials with elevated pre-stimulus cingulo-opercular BOLD, consistent with an adaptive control framework. Cingulo-opercular adaptive control estimates appeared higher for participants with better gap sensitivity and lower response bias, irrespective of age, which suggests that this mechanism can benefit performance across the lifespan under conditions that limit age-related performance differences.

Age Effects on Cochlear Reflectance in Adults.

OBJECTIVES: Cochlear reflectance (CR) is the cochlear contribution to ear-canal reflectance. CR is a type of otoacoustic emission that is calculated as a transfer function between forward pressure and reflected pressure. The purpose of this study was to assess effects of age on CR in adults and interactions among age, sex, and hearing loss. DESIGN: Data were collected from 60 adults selected for their age (e.g., 20-29, 30-39, 40-49, 50-59, 60-69, 70-79 years) and normal middle ear status. A wideband noise stimulus presented at three stimulus levels (30, 40, 50 dB SPL) was used to elicit CR. Half-octave bands of CR signal magnitude (CRM), CR noise, and the CR signal-to-noise ratio (CR-SNR) were extracted from the wideband CR response. Regression analyses were conducted to assess interactions among CR, age, sex, and pure-tone thresholds at closely matched frequency bands across stimulus levels. RESULTS: Although increased age was generally associated with lower CRM and CR-SNR at some band frequencies and stimulus levels, no significant effects of age remained after controlling for effects of pure-tone thresholds. Increases in pure-tone thresholds were associated with lower CRM and CR-SNR at most frequency bands and stimulus levels. Effects of hearing sensitivity were significant at some frequencies and levels after controlling for age and sex. CONCLUSIONS: When effects of age were controlled, adults with better hearing had significantly larger CRM and CR-SNR than those with poorer hearing. In contrast, when effects of hearing were controlled, no significant effects of age on CRM and CR-SNR remained.

Neuroanatomical structures supporting lexical diversity, sophistication, and phonological word features during discourse.

Deficits in lexical retrieval are commonly observed in individuals with post-stroke aphasia. Successful lexical retrieval is related to lexical diversity, lexical sophistication, and phonological word properties; however, the crucial brain regions supporting these different features are not fully understood. We performed MRI-based lesion symptom mapping in 58 individuals with a chronic left hemisphere stroke to assess how regional damage relates to spoken discourse-extracted measures of lexical diversity, lexical sophistication, and phonological word properties. For discourse transcription and word feature analysis, we used the Computerized Language Analysis (CLAN) program, Stanford Core Natural Language Processing, Irvine Phonotactic Online Dictionary, Lexical Complexity Analyzer, and Gramulator. Lesions involving the left posterior insula and supramarginal gyri and inferior fronto-occipital fasciculus were significant predictors of utterances with, on average, lower lexical diversity. Low lexical sophistication was associated with damage to the left pole of the superior temporal gyrus. Production of words with lower phonological complexity (fewer phonemes, higher phonological similarity) was associated with damage to the left supramarginal gyrus. Our findings indicate that discourse-extracted features of lexical retrieval depend on the integrity of specific brain regions involving insular and peri-Sylvian areas. The identified regions provide insight into potentially underlying mechanisms of lexically diverse, sophisticated and phonologically complex words produced during discourse.

Age-Related Hearing Loss Associations With Changes in Brain Morphology.

Age-related hearing loss has been associated with varied auditory cortex morphology in human neuroimaging studies. These findings have suggested that peripheral auditory system declines cause changes in brain morphology but could also be due to latent variables that affect the auditory periphery and brain. The current longitudinal study was designed to evaluate these explanations for pure-tone threshold and brain morphology associations. Thirty adults (mean age at Time 1 = 64.12 ± 10.32 years) were studied at two time points (average duration between visits = 2.62 ± 0.81 years). Small- to medium-effect size associations were observed between high-frequency pure-tone thresholds and auditory cortex gray matter volume at each time point. Although there were significant longitudinal changes in low- and high-frequency hearing measures and brain morphology, those longitudinal changes were not significantly correlated across participants. High-frequency hearing measures at Time 1 were significantly related to more lateral ventricle expansion, such that participants with higher measures exhibited larger increases in ventricle size. This ventricle effect was statistically independent of high-frequency hearing associations with auditory cortex morphology. Together, these results indicate that there are at least two mechanisms for associations between age-related hearing loss and brain morphology. Potential explanations for a direct hearing loss effect on brain morphology, as well as latent variables that likely affect both the inner ear and brain, are discussed.