Duplicated Heschl's gyrus associations with phonological decoding.

The reason(s) for why a complete duplication of the left hemisphere Heschl's gyrus (HG) has been observed in people with reading disability are unclear. This study was designed to replicate and advance understanding of the HG and phonological decoding association, as well as test competing hypotheses that this HG duplication association is specifically localized to the HG or could be due to co-occurring atypical development of other brain regions that support reading and language development. Participants were selected on the basis of having a duplicated left hemisphere HG (N = 96) or a single HG (N = 96) and matched according to age, sex, and research site in this multi-site study. Duplicated and single HG morphology specific templates were created to determine the extent to which HG sizes were related to phonological decoding within each HG morphology group. The duplicated HG group had significantly lower phonological decoding (F = 4.48, p = 0.04) but not verbal IQ (F = 1.39, p = 0.41) compared to the single HG group. In addition, larger HG were significantly associated with lower phonological decoding in the duplicated HG group, with effects driven by the size of the lateral HG after controlling for age, sex, research site, and handedness (ps < 0.05). Brain regions that exhibited structural covariance with HG did not clearly explain the HG and phonological decoding associations. Together, the results suggest that presence of a duplicated HG indicates some risk for lower phonological decoding ability compared to verbal IQ, but the reason(s) for this association remain unclear.

Gray matter and episodic memory associations with olfaction in middle-aged to older adults.

BACKGROUND: Age-related declines in olfaction contribute to low quality of life and appear to occur with declines in cognitive function, including diminished episodic memory. We tested the hypothesis that low gray matter volume within cortical regions that support olfaction and episodic memory can explain age-related differences in olfactory and episodic memory functions. METHODS: T1-weighted images, Sniffin' Sticks olfactory measures, and the NIH Toolbox-Cognition Battery were administered to 131 middle-aged to older adults (50-86 years; 66% female). Correlation was used to examine the associations between these measures. A network-based image processing approach was then used to examine the degree to which spatial patterns of gray matter variance were related to the olfactory and cognitive measures. Structural equation modeling was used to characterize the relative specificity of olfactory, cognitive, gray matter, and aging associations. RESULTS: Olfactory threshold, discrimination, and identification exhibited small to medium effect size associations with episodic memory performance (rs = 0.27-0.42, ps < 0.002). Gray matter volume within medial temporal and orbitofrontal cortex was also related to olfactory (discrimination and identification) and episodic memory function (rs = 0.21-0.36, ps < 0.019). Age and episodic memory explained the same variance in olfaction that was explained by the medial temporal and orbitofrontal pattern of gray matter volume. CONCLUSIONS: The results of this cross-sectional study suggest that identifying mechanisms contributing to differences in medial temporal and orbitofrontal cortex will advance our understanding of co-morbid olfactory and cognitive declines.

The Stria Vascularis in Mice and Humans Is an Early Site of Age-Related Cochlear Degeneration, Macrophage Dysfunction, and Inflammation.

Age-related hearing loss, or presbyacusis, is a common degenerative disorder affecting communication and quality of life for millions of older adults. Multiple pathophysiologic manifestations, along with many cellular and molecular alterations, have been linked to presbyacusis; however, the initial events and causal factors have not been clearly established. Comparisons of the transcriptome in the lateral wall (LW) with other cochlear regions in a mouse model (of both sexes) of "normal" age-related hearing loss revealed that early pathophysiological alterations in the stria vascularis (SV) are associated with increased macrophage activation and a molecular signature indicative of inflammaging, a common form of immune dysfunction. Structure-function correlation analyses in mice across the lifespan showed that the age-dependent increase in macrophage activation in the stria vascularis is associated with a decline in auditory sensitivity. High-resolution imaging analysis of macrophage activation in middle-aged and aged mouse and human cochleas, along with transcriptomic analysis of age-dependent changes in mouse cochlear macrophage gene expression, support the hypothesis that aberrant macrophage activity is an important contributor to age-dependent strial dysfunction, cochlear pathology, and hearing loss. Thus, this study highlights the SV as a primary site of age-related cochlear degeneration and aberrant macrophage activity and dysregulation of the immune system as early indicators of age-related cochlear pathology and hearing loss. Importantly, novel new imaging methods described here now provide a means to analyze human temporal bones in a way that had not previously been feasible and thereby represent a significant new tool for otopathological evaluation.SIGNIFICANCE STATEMENT Age-related hearing loss is a common neurodegenerative disorder affecting communication and quality of life. Current interventions (primarily hearing aids and cochlear implants) offer imperfect and often unsuccessful therapeutic outcomes. Identification of early pathology and causal factors is crucial for the development of new treatments and early diagnostic tests. Here, we find that the SV, a nonsensory component of the cochlea, is an early site of structural and functional pathology in mice and humans that is characterized by aberrant immune cell activity. We also establish a new technique for evaluating cochleas from human temporal bones, an important but understudied area of research because of a lack of well-preserved human specimens and difficult tissue preparation and processing approaches.

Performance Monitoring and Cognitive Inhibition during a Speech-in-Noise Task in Older Listeners.

The goal of this study was to examine the effect of hearing loss on theta and alpha electroencephalography (EEG) frequency power measures of performance monitoring and cognitive inhibition, respectively, during a speech-in-noise task. It was hypothesized that hearing loss would be associated with an increase in the peak power of theta and alpha frequencies toward easier conditions compared to normal hearing adults. The shift would reflect how hearing loss modulates the recruitment of listening effort to easier listening conditions. Nine older adults with normal hearing (ONH) and 10 older adults with hearing loss (OHL) participated in this study. EEG data were collected from all participants while they completed the words-in-noise task. It hypothesized that hearing loss would also have an effect on theta and alpha power. The ONH group showed an inverted U -shape effect of signal-to-noise ratio (SNR), but there were limited effects of SNR on theta or alpha power in the OHL group. The results of the ONH group support the growing body of literature showing effects of listening conditions on alpha and theta power. The null results of listening condition in the OHL group add to a smaller body of literature, suggesting that listening effort research conditions should have near ceiling performance.

Structural Covariance of the Duplicated Heschl's Gyrus: A Sulcal/Gyral Template Morphology Approach.

Heschl's gyrus (HG) can occur as a single gyrus or with a completely duplicated posterior HG that has been related to a variety of abilities and disorders. Voxel-based studies typically involve the normalization of these qualitatively different HG types, thus making it difficult to evaluate the contribution of sulcal/gyral variability to voxel-based effects and perhaps obscuring some effects. To examine the structural covariance of single and duplicated HG, templates were created for the left single and duplicated HG. Structural covariance analysis with a Jacobian measure of volumetric displacement demonstrated consistent spatial covariance with homologous structure in the right hemisphere across qualitatively different HG morphology. These results suggest that HG duplication is aptly named with respect to cortical structure variation and demonstrate a multi-template approach for studying qualitatively unique brain function and structure linked to perceptual and cognitive functions. Highlights: Qualitatively unique sulcal/gyral features can affect voxel-based analyses.Heschl's gyrus is highly variable across people.Morphology-specific templates were created to study Heschl's gyrus structural covariance.Single and duplicated Heschl's gyrus exhibited a similar pattern of covariance.

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.

Locus coeruleus and dorsal cingulate morphology contributions to slowed processing speed.

Slowed information processing speed is a defining feature of cognitive aging. Nucleus locus coeruleus (LC) and medial prefrontal regions are targets for understanding slowed processing speed because these brain regions influence neural and behavioral response latencies through their roles in optimizing task performance. Although structural measures of medial prefrontal cortex have been consistently related to processing speed, it is unclear if 1) declines in LC structure underlie this association because of reciprocal connections between LC and medial prefrontal cortex, or 2) if LC declines provide a separate explanation for age-related changes in processing speed. LC and medial prefrontal structural measures were predicted to explain age-dependent individual differences in processing speed in a cross-sectional sample of 43 adults (19-79 years; 63% female). Higher turbo-spin echo LC contrast, based on a persistent homology measure, and greater dorsal cingulate cortical thickness were significantly and each uniquely related to faster processing speed. However, only dorsal cingulate cortical thickness appeared to statistically mediate age-related differences in processing speed. The results suggest that individual differences in cognitive processing speed can be attributed, in part, to structural variation in nucleus LC and medial prefrontal cortex, with the latter key to understanding why older adults exhibit slowed processing speed.

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.

Unsupervised Clustering of Olfactory Phenotypes.

BACKGROUND: Current clinical classifications of olfactory function are based primarily upon a percentage of correct answers in olfactory identification testing. This simple classification provides little insight into etiologies of olfactory loss, associated comorbidities, or impact on the quality of life (QOL). METHODS: Community-based subjects underwent olfactory psychophysical testing using Sniffin Sticks to measure threshold (T), discrimination (D), and identification (I). The cognitive screening was performed using Mini-Mental Status Examination (MMSE). Unsupervised clustering was performed based upon T, D, I, and MMSE. Post hoc differences in demographics, comorbidities, and QOL measures were assessed. RESULTS: Clustering of 219 subjects, mean age 51 years (range 20-93 years) resulted in 4 unique clusters. Cluster 1 was the largest and predominantly younger normosmics. Cluster 2 had the worst olfaction with impairment in nearly all aspects of olfaction and decreased MMSE scores. This cluster had higher rates of smoking, heart disease, and cancer and had the worst olfactory-specific QOL. Cluster 3 had normal MMSE with relative preservation of D and I, but severely impaired T. This cluster had higher rates of smoking and heart disease with moderately impaired QOL. Cluster 4 was notable for the worst MMSE scores, but general preservation of D and I with moderate loss of T. This cluster had higher rates of Black subjects, diabetes, and viral/traumatic olfactory loss. CONCLUSION: Unsupervised clustering based upon detailed olfactory testing and cognitive testing results in clinical phenotypes with unique risk factors and QOL impacts. These clusters may provide additional information regarding etiologies and subsequent therapies to treat olfactory loss.

Impact of Effortful Word Recognition on Supportive Neural Systems Measured by Alpha and Theta Power.

OBJECTIVES: The goal of this study was to use theta and alpha electroencephalography (EEG) frequency power and self-report measures to examine performance monitoring, cognitive inhibition, and perceived effort required for speech understanding in noise. It was hypothesized that with a linear increase in word recognition task difficulty, there would be a linear increase in listening effort and word recognition performance would decrease in the challenging conditions. In addition, theta and alpha power would have an inverted U-shape across easy to challenging listening conditions. The inverted U-shape would reflect the neural underpinnings of listening effort that cannot be measured by task performance alone. DESIGN: EEG data were collected in 34 normal-hearing adults (18 to 33 years old) during the Words-In-Noise (WIN) test, which was presented in sound field. EEG frequency data were averaged and analyzed at three frontal channels for theta power (4 to 8 Hz), which is thought to reflect performance monitoring, and three parietal channels for alpha power (8 to 12 Hz), which is thought to reflect cognitive inhibition. A ten-point visual analog scale was administered after each WIN signal-to-noise ratio (SNR) condition to capture self-reported required and invested listening effort (RLE and ILE, respectively). The WIN SNR conditions were presented in descending and random order. RESULTS: The SNR presentation (descending or random SNR) had a null effect on word recognition performance; however, presentation did have an effect on theta power, alpha power, and ILE. When controlling for presentation, there were significant effects of SNR and presentation on both theta and alpha frequency power. Theta and alpha power had an inverted U-shape as a function of SNR from easy to challenging, with peak power in the moderate SNR conditions. RLE and ILE both significantly increased as task difficulty increased as expected; however, RLE showed a stronger relation to task performance than ILE. Alpha power was a significant predictor of RLE, ILE, and WIN performance when controlling for SNR. CONCLUSIONS: The elevated theta and alpha power in the easy to moderate SNRs and alpha power predicting self-reported listening effort suggest the activation of supportive neural systems during word recognition that could be considered a marker of listening effort. Moreover, the measures of neural support systems and listening effort were independent from task performance, which is a key element to further understanding the neural bases for listening effort. In the context of the broader literature, these results are consistent with (1) a parietal alpha role in supporting inhibitory control to suppress irrelevant information and (2) a frontal theta role in supporting performance monitoring in difficult listening conditions where speech recognition is feasible.

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.

Neoadjuvant Chemotherapy Induces Genomic and Transcriptomic Changes in Ovarian Cancer.

The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. Here we performed a cohort study including 34 patients with advanced stage IIIC or IV HGSOC to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy. RNA sequencing and panel DNA sequencing of 596 cancer-related genes was performed on paired formalin-fixed paraffin-embedded specimens collected before and after chemotherapy, and differentially expressed genes (DEG) and copy-number variations (CNV) in pre- and post-chemotherapy samples were identified. Following tissue and sequencing quality control, the final patient cohort consisted of 32 paired DNA and 20 paired RNA samples. Genomic analysis of paired samples did not reveal any recurrent chemotherapy-induced mutations. Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy-resistant specimens. AP-1 transcription factor family genes (FOS, FOSB, FRA-1) were particularly upregulated in chemotherapy-resistant samples. CNV analysis identified recurrent 11q23.1 amplification, which encompasses SIK2. In vitro, combined treatment with AP-1 or SIK2 inhibitors with carboplatin or paclitaxel demonstrated synergistic effects. These data suggest that AP-1 activity and SIK2 copy-number amplification are induced by chemotherapy and may represent mechanisms by which chemotherapy resistance evolves in HGSOC. AP-1 and SIK2 are druggable targets with available small molecule inhibitors and represent potential targets to circumvent chemotherapy resistance. SIGNIFICANCE: Genomic and transcriptomic analyses identify increased AP-1 activity and SIK2 copy-number amplifications in resistant ovarian cancer following neoadjuvant chemotherapy, uncovering synergistic effects of AP-1 and SIK2 inhibitors with chemotherapy.

Isolation of Normal and Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) play important roles in regulating tumor progression, metastasis, and response to therapies. Accurately modeling the interplay between cancer cells and the tumor microenvironment (TME) requires the use of primary cells from patient samples. Here we describe methods for the isolation of both primary CAFs and fibroblasts from omental tissue using a combination of mechanical dissociation and enzymatic digestion. Primary cells can be used for functional and mechanistic studies and may be safely cryopreserved.