Auditory neural processing in children living with HIV uncovers underlying central nervous system dysfunction.

OBJECTIVE: Central nervous system (CNS) damage from HIV infection or treatment can lead to developmental delays and poor educational outcomes in children living with HIV (CLWH). Early markers of central nervous system dysfunction are needed to target interventions and prevent life-long disability. The frequency following response (FFR) is an auditory electrophysiology test that can reflect the health of the central nervous system. In this study, we explore whether the FFR reveals auditory central nervous system dysfunction in CLWH. STUDY DESIGN: Cross-sectional analysis of an ongoing cohort study. Data were from the child's first visit in the study. SETTING: The infectious disease center in Dar es Salaam, Tanzania. METHODS: We collected the FFR from 151 CLWH and 151 HIV-negative children. To evoke the FFR, three speech syllabi (/da/, /ba/, /ga/) were played monaurally to the child's right ear. Response measures included neural timing (peak latencies), strength of frequency encoding (fundamental frequency and first formant amplitude), encoding consistency (inter-response consistency), and encoding precision (stimulus-to-response correlation). RESULTS: CLWH showed smaller first formant amplitudes ( P  < 0.0001), weaker inter-response consistencies ( P  < 0.0001) and smaller stimulus to response correlations ( P  < 0.0001) than FFRs from HIV-negative children. These findings generalized across the three speech stimuli with moderately strong effect sizes (partial η2 ranged from 0.061 to 0.094). CONCLUSION: The FFR shows auditory central nervous system dysfunction in CLWH. Neural encoding of auditory stimuli was less robust, more variable, and less accurate. As the FFR is a passive and objective test, it may offer an effective way to assess and detect central nervous system function in CLWH.

Subconcussion revealed by sound processing in the brain.

Introduction/Purpose: We tested the hypothesis that an objective measure of auditory processing reveals a history of head trauma that does not meet the clinical definition of concussion. Methods: Division I collegiate student-athletes (n = 709) across 19 sports were divided into groups, based on their sport, using prevailing classifications of "contact" (317 males, 212 females) and "noncontact" (58 males, 122 females). Participants were evaluated using the frequency-following response (FFR) to speech. The amplitude of FFR activity in a frequency band corresponding to the fundamental frequency (F0)-the voice pitch-of the speech stimulus, an outcome reduced in individuals with concussions, was critically examined. Results: We found main effects of contact level and sex. The FFR-F0 was smaller in contact athletes than noncontact athletes and larger in females than males. There was a contact by sex interaction, with the FFR-F0 of males in the contact group being smaller than the three other groups. Secondary analyses found a correlation between FFR-F0 and length of participation in contact sports in male athletes. Conclusion: These findings suggest that the disruption of sensory processing in the brain can be observed in individuals without a concussion but whose sport features regular physical contact. This evidence identifies sound processing in the brain as an objective marker of subconcussion in athletes.

Peripheral Auditory Function in Tanzanian Children Living With HIV With Clinically Normal Hearing.

Importance: Despite normal audiometry, adults living with HIV have lower distortion product otoacoustic emissions (DPOAEs) compared with HIV-negative controls, but the degree of these differences in children living with HIV is unknown. If subclinical auditory deficits are present, results could affect developmental outcomes in children living with HIV (CLWH). Objective: To compare DPOAEs and auditory brainstem responses (ABR) between 2 age- and sex-matched groups of younger children with normal audiometry, 1 infected with HIV and the other uninfected. Design, Setting, and Participants: Cohort study in an infectious disease center in Dar es Salaam, Tanzania. Participants included 340 Tanzanian children aged 3 to 9 years with clinically normal hearing, type A tympanograms bilaterally, and air-conduction thresholds of 20 dB HL or less from 0.5 to 8 kHz. Participants in the cohort repeated testing approximately every 6 months (approximately 2.2 sessions per participant) for a total of 744 total observations. Data were analyzed from March 2020 to January 2022. Main Outcomes and Measures: DPOAE amplitudes from 1.5 to 8 kHz using an f2 to f1 ratio of 1.2 and L1/L2 values of 65/55 dB sound pressure level and click-evoked ABR using a slow (21.1/s) and fast (61.1/s) click rate. Results: A total of 141 CLWH (70 female participants [49.3%]; mean [SD] age, 7.24 [1.67] years) and 199 HIV-negative individuals (99 female participants [49.7%]; mean [SD] age, 7.26 [1.44] years) participated in the study. The groups did not differ significantly in age, static immittance, or air-conduction thresholds. HIV status was independently associated with approximately 1.4 dB (95% CI, -3.28 to 0.30 dB) to 3.8 dB (95% CI, 6.03 to -1.99 dB) lower DPOAE amplitudes at 6 and 8 kHz bilaterally and 0.28 µV (95% CI, 0.01 to 0.33 µV) lower ABR wave V amplitudes in the right ear. Conclusions and Relevance: Consistent with previous findings in young adults, CLWH had slightly, but reliably, lower DPOAEs and ABR wave V amplitudes than HIV-negative controls. The magnitude of these differences was small, but results suggest an early and consistent association between HIV infection or treatment and outer hair cell and auditory brainstem responses in children as young as 3 years. These subclinical changes suggest tracking both auditory function and development outcomes in CLWH is warranted.

Preliteracy assessment in children living with HIV in Tanzania: comparison to results from children living without HIV in Tanzania and the United States.

OBJECTIVE: Children with HIV (CWH) are at increased risk for cognitive and developmental delays. Whether HIV affects literacy development, however, remains unknown. Rapid automatized naming (RAN) tasks offer the simplest preliteracy assessment a child can perform that predicts future reading skills across languages. DESIGN AND METHODS: RAN performance was analyzed cross-sectionally on 473 children (249 children without HIV and 217 CWH; ages 3-9) drawn from a longitudinal study in Tanzania. These data were compared to results from 341 normally developing children without HIV (ages 3-8) from the United States. Participants performed two RAN subtests: colors and objects. RESULTS: RAN object completion was greater than for the RAN color in Tanzanian children. CWH were less likely to complete either subtest and performed worse on the object subtest compared to Tanzanian children without HIV. Compared to the US cohort, the Tanzanian cohort was less likely to complete both subtests - in particular the colors subtest - and showed more variability in responses at younger ages. After approximately age 6, however, the trajectory of improvement between the United States and Tanzania was similar. CONCLUSIONS: CWH performed worse on this per-literacy test, indicating literacy skill development in CWH needs further study. The differences between US and Tanzanian results likely reflect variability in when children learn to name colors and objects. The trajectory of improvement between countries became more similar as the children aged. This study motivates further longitudinal analyses aimed at assessing the developmental trajectory of the RAN, its predictive ability for reading skills, and its link with other preliteracy and cognitive skills.

Neural Processing of Speech Sounds in ASD and First-Degree Relatives.

Efficient neural encoding of sound plays a critical role in speech and language, and when impaired, may have reverberating effects on communication skills. This study investigated disruptions to neural processing of temporal and spectral properties of speech in individuals with ASD and their parents and found evidence of inefficient temporal encoding of speech sounds in both groups. The ASD group further demonstrated less robust neural representation of spectral properties of speech sounds. Associations between neural processing of speech sounds and language-related abilities were evident in both groups. Parent-child associations were also detected in neural pitch processing. Together, results suggest that atypical neural processing of speech sounds is a heritable ingredient contributing to the ASD language phenotype.

OCT Meets micro-CT: A Subject-Specific Correlative Multimodal Imaging Workflow for Early Chick Heart Development Modeling.

Structural and Doppler velocity data collected from optical coherence tomography have already provided crucial insights into cardiac morphogenesis. X-ray microtomography and other ex vivo methods have elucidated structural details of developing hearts. However, by itself, no single imaging modality can provide comprehensive information allowing to fully decipher the inner workings of an entire developing organ. Hence, we introduce a specimen-specific correlative multimodal imaging workflow combining OCT and micro-CT imaging which is applicable for modeling of early chick heart development-a valuable model organism in cardiovascular development research. The image acquisition and processing employ common reagents, lab-based micro-CT imaging, and software that is free for academic use. Our goal is to provide a step-by-step guide on how to implement this workflow and to demonstrate why those two modalities together have the potential to provide new insight into normal cardiac development and heart malformations leading to congenital heart disease.

Athleticism and sex impact neural processing of sound.

Biology and experience both influence the auditory brain. Sex is one biological factor with pervasive effects on auditory processing. Females process sounds faster and more robustly than males. These differences are linked to hormone differences between the sexes. Athleticism is an experiential factor known to reduce ongoing neural noise, but whether it influences how sounds are processed by the brain is unknown. Furthermore, it is unknown whether sports participation influences auditory processing differently in males and females, given the well-documented sex differences in auditory processing seen in the general population. We hypothesized that athleticism enhances auditory processing and that these enhancements are greater in females. To test these hypotheses, we measured auditory processing in collegiate Division I male and female student-athletes and their non-athlete peers (total n = 1012) using the frequency-following response (FFR). The FFR is a neurophysiological response to sound that reflects the processing of discrete sound features. We measured across-trial consistency of the response in addition to fundamental frequency (F0) and harmonic encoding. We found that athletes had enhanced encoding of the harmonics, which was greatest in the female athletes, and that athletes had more consistent responses than non-athletes. In contrast, F0 encoding was reduced in athletes. The harmonic-encoding advantage in female athletes aligns with previous work linking harmonic encoding strength to female hormone levels and studies showing estrogen as mediating athlete sex differences in other sensory domains. Lastly, persistent deficits in auditory processing from previous concussive and repetitive subconcussive head trauma may underlie the reduced F0 encoding in athletes, as poor F0 encoding is a hallmark of concussion injury.

Peripheral Auditory Function in Young HIV-Positive Adults With Clinically Normal Hearing.

OBJECTIVE: Little is known about peripheral auditory function in young adults with HIV, who might be expected to show early evidence of hearing loss if HIV infection or treatment does affect peripheral function. The goal of this study was to compare peripheral auditory function in 2 age- and gender-matched groups of young adults with clinically normal hearing with and without HIV. STUDY DESIGN: Matched cohort study with repeated measures. SETTING: Infectious disease center in Dar es Salaam, Tanzania. METHODS: Participants included HIV-positive (n = 38) and HIV-negative (n = 38) adults aged 20 to 30 years who had clinically normal hearing, defined as type A tympanograms, air conduction thresholds ≤25 dB HL bilaterally from 0.5 to 8 kHz, and distortion product otoacoustic emissions (DPOAEs) >6 dB above the noise floor bilaterally from 1.5 to 8 kHz. Participants were tested multiple times over 6-month intervals (average, 2.7 sessions/participant) for a total of 208 observations. Primary outcome measures included tympanograms, air conduction audiograms, DPOAEs, and click-evoked auditory brainstem responses. RESULTS: HIV groups did not significantly differ in age, static immittance, or air conduction thresholds. HIV-positive status was independently associated with approximately 3.7-dB lower DPOAE amplitudes from 2 to 8 kHz (95% CI, 1.01-6.82) in both ears and 0.04-µV lower (95% CI, 0.003-0.076) auditory brainstem response wave I amplitudes in the right ear. CONCLUSION: Young adults living with HIV have slightly but reliably smaller DPOAEs and auditory brainstem response wave I amplitudes than matched HIV-negative controls. The magnitude of these differences is small, but these results support measuring peripheral auditory function in HIV-positive individuals as they age.

Multiple Cases of Auditory Neuropathy Illuminate the Importance of Subcortical Neural Synchrony for Speech-in-noise Recognition and the Frequency-following Response.

OBJECTIVES: The role of subcortical synchrony in speech-in-noise (SIN) recognition and the frequency-following response (FFR) was examined in multiple listeners with auditory neuropathy. Although an absent FFR has been documented in one listener with idiopathic neuropathy who has severe difficulty recognizing SIN, several etiologies cause the neuropathy phenotype. Consequently, it is necessary to replicate absent FFRs and concomitant SIN difficulties in patients with multiple sources and clinical presentations of neuropathy to elucidate fully the importance of subcortical neural synchrony for the FFR and SIN recognition. DESIGN: Case series. Three children with auditory neuropathy (two males with neuropathy attributed to hyperbilirubinemia, one female with a rare missense mutation in the OPA1 gene) were compared to age-matched controls with normal hearing (52 for electrophysiology and 48 for speech recognition testing). Tests included standard audiological evaluations, FFRs, and sentence recognition in noise. The three children with neuropathy had a range of clinical presentations, including moderate sensorineural hearing loss, use of a cochlear implant, and a rapid progressive hearing loss. RESULTS: Children with neuropathy generally had good speech recognition in quiet but substantial difficulties in noise. These SIN difficulties were somewhat mitigated by a clear speaking style and presenting words in a high semantic context. In the children with neuropathy, FFRs were absent from all tested stimuli. In contrast, age-matched controls had reliable FFRs. CONCLUSION: Subcortical synchrony is subject to multiple forms of disruption but results in a consistent phenotype of an absent FFR and substantial difficulties recognizing SIN. These results support the hypothesis that subcortical synchrony is necessary for the FFR. Thus, in healthy listeners, the FFR may reflect subcortical neural processes important for SIN recognition.

Nonverbal cognitive assessment of children in Tanzania with and without HIV.

Children living with HIV can experience cognitive difficulties. Most neuropsychological tests have been constructed in Western languages, meaning they may not be appropriate for use in non-Western settings. To address this, we used an entirely nonverbal measure of cognitive ability in a sub-Saharan African sample. For this cross-sectional analysis, 316 children (162 HIV+ and 154 HIV-, ages 3-9) completed the Leiter-3 as part of a larger study in Dar es Salaam, Tanzania. Statistical tests included analysis of covariance and multiple linear regression to account for environmental variables. HIV+ children performed worse than HIV - controls on two composite scores: Nonverbal IQ (p < .001) and Processing Speed (p < 0.001). Similar trends were observed on core subtests. Multiple linear regression models revealed that age, socioeconomic status, and school attendance predicted all Leiter-3 test composites. Critically, the addition of HIV status to the models improved prediction of Nonverbal IQ (∆R2 = 0.03, p = .001) and Processing Speed (∆R2 = 0.06, p < .001). Children living with HIV performed worse than HIV- controls on most Leiter-3 measures. While age, SES, and school attendance predicted Leiter-3 performance, HIV status improved prediction capabilities when added to the model. The Leiter-3 may offer a viable measure of cognitive ability in non-Western settings that can be used in its original form without translation.

Anuran development: A reinvestigation of the conus arteriosus and gill formation in Bufo bufo throughout metamorphosis using micro-CT.

Using high-resolution X-ray micro-CT imaging of whole Bufo bufo specimens, we acquired detailed 3D descriptions of the changing morphology of the cardiac outflow structures, in particular the conus arteriosus through larval development and the transition. Previous findings regarding anuran conal structures were contradictory, depending on the specifics of the 2D imaging methods used by different authors. Our descriptions of conal morphology at different developmental stages show that early tadpoles initially only have one opening at the ventricular-conal junction and only one cavum within their conus; however, the forming septum coni soon divides the conus into two chambers, the cavum pulmocutaneum and the cavum aorticum. This is accompanied by the development of a second small opening at the ventricular-conal junction. The separated chambers continue into the aortic arches. Following the aortic arches into the area where gills will form, we describe how blood vessels associated with the external gills develop from vessels arising from the truncus arteriosus. The external gills soon undergo partial absorption. During the transition from external to internal gills, the gill filaments retreat asymmetrically into a gill chamber formed by a hyoidal cover contacting the animal's ventral side, leaving only a single opening on the animal's left side, the opercular spout. B. bufo retains its internal gills up to metamorphic climax, with the aortic arches arising from the conus arteriosus still leading into the gills. Our 3D image data are publicly available and will provide a sound morphological basis for future studies.

Listening in the Moment: How Bilingualism Interacts With Task Demands to Shape Active Listening.

While there is evidence for bilingual enhancements of inhibitory control and auditory processing, two processes that are fundamental to daily communication, it is not known how bilinguals utilize these cognitive and sensory enhancements during real-world listening. To test our hypothesis that bilinguals engage their enhanced cognitive and sensory processing in real-world listening situations, bilinguals and monolinguals performed a selective attention task involving competing talkers, a common demand of everyday listening, and then later passively listened to the same competing sentences. During the active and passive listening periods, evoked responses to the competing talkers were collected to understand how online auditory processing facilitates active listening and if this processing differs between bilinguals and monolinguals. Additionally, participants were tested on a separate measure of inhibitory control to see if inhibitory control abilities related with performance on the selective attention task. We found that although monolinguals and bilinguals performed similarly on the selective attention task, the groups differed in the neural and cognitive processes engaged to perform this task, compared to when they were passively listening to the talkers. Specifically, during active listening monolinguals had enhanced cortical phase consistency while bilinguals demonstrated enhanced subcortical phase consistency in the response to the pitch contours of the sentences, particularly during passive listening. Moreover, bilinguals' performance on the inhibitory control test related with performance on the selective attention test, a relationship that was not seen for monolinguals. These results are consistent with the hypothesis that bilinguals utilize inhibitory control and enhanced subcortical auditory processing in everyday listening situations to engage with sound in ways that are different than monolinguals.

Sex differences in auditory processing vary across estrous cycle.

In humans, females process a sound's harmonics more robustly than males. As estrogen regulates auditory plasticity in a sex-specific manner in seasonally breeding animals, estrogen signaling is one hypothesized mechanism for this difference in humans. To investigate whether sex differences in harmonic encoding vary similarly across the reproductive cycle of mammals, we recorded frequency-following responses (FFRs) to a complex sound in male and female rats. Female FFRs were collected during both low and high levels of circulating estrogen during the estrous cycle. Overall, female rodents had larger harmonic encoding than male rodents, and greater harmonic strength was seen during periods of greater estrogen production in the females. These results argue that hormonal differences, specifically estrogen, underlie sex differences in harmonic encoding in rodents and suggest that a similar mechanism may underlie differences seen in humans.

Auditory Cortical Changes Precede Brainstem Changes During Rapid Implicit Learning: Evidence From Human EEG.

The auditory system is sensitive to stimulus regularities such as frequently occurring sounds and sound combinations. Evidence of regularity detection can be seen in how neurons across the auditory network, from brainstem to cortex, respond to the statistical properties of the soundscape, and in the rapid learning of recurring patterns in their environment by children and adults. Although rapid auditory learning is presumed to involve functional changes to the auditory network, the chronology and directionality of changes are not well understood. To study the mechanisms by which this learning occurs, auditory brainstem and cortical activity was simultaneously recorded via electroencephalogram (EEG) while young adults listened to novel sound streams containing recurring patterns. Neurophysiological responses were compared between easier and harder learning conditions. Collectively, the behavioral and neurophysiological findings suggest that cortical and subcortical structures each provide distinct contributions to auditory pattern learning, but that cortical sensitivity to stimulus patterns likely precedes subcortical sensitivity.

Non-stimulus-evoked activity as a measure of neural noise in the frequency-following response.

BACKGROUND: The frequency-following response, or FFR, is a neurophysiologic response that captures distinct aspects of sound processing. Like all evoked responses, FFR is susceptible to electric and myogenic noise contamination during collection. Click-evoked auditory brainstem response collection standards have been adopted for FFR collection, however, whether these standards sufficiently limit FFR noise contamination is unknown. Thus, a critical question remains: to what extent do distinct FFR components reflect noise contamination? This is especially relevant for prestimulus amplitude (i.e., activity preceding the evoked response), as this measure has been used to index both noise contamination and neural noise. NEW METHOD: We performed two experiments. First, using >1000 young-adult FFRs, we ran regressions to determine the variance explained by myogenic and electrical noise, as indexed by artifact rejection count and electrode impedance, on each FFR component. Second, we reanalyzed prestimulus amplitude differences attributed to athletic experience and socioeconomic status, adding covariates of artifact rejection and impedance. RESULTS: We found that non-neural noise marginally contributed to FFR components and could not explain group differences on prestimulus amplitude. COMPARISON WITH EXISTING METHOD: Prestimulus amplitude has been considered a measure of non-neural noise contamination. However, non-neural noise was not the sole contributor to variance in this measure and did not explain group differences. CONCLUSIONS: Results from the two experiments suggest that the effects of non-neural noise on FFR components are minimal and do not obscure individual differences in the FFR and that prestimulus amplitude indexes neural noise.

Auditory neurophysiological development in early childhood: A growth curve modeling approach.

OBJECTIVE: During early childhood, the development of communication skills, such as language and speech perception, relies in part on auditory system maturation. Because auditory behavioral tests engage cognition, mapping auditory maturation in the absence of cognitive influence remains a challenge. Furthermore, longitudinal investigations that capture auditory maturation within and between individuals in this age group are scarce. The goal of this study is to longitudinally measure auditory system maturation in early childhood using an objective approach. METHODS: We collected frequency-following responses (FFR) to speech in 175 children, ages 3-8 years, annually for up to five years. The FFR is an objective measure of sound encoding that predominantly reflects auditory midbrain activity. Eliciting FFRs to speech provides rich details of various aspects of sound processing, namely, neural timing, spectral coding, and response stability. We used growth curve modeling to answer three questions: 1) does sound encoding change across childhood? 2) are there individual differences in sound encoding? and 3) are there individual differences in the development of sound encoding? RESULTS: Subcortical auditory maturation develops linearly from 3-8 years. With age, FFRs became faster, more robust, and more consistent. Individual differences were evident in each aspect of sound processing, while individual differences in rates of change were observed for spectral coding alone. CONCLUSIONS: By using an objective measure and a longitudinal approach, these results suggest subcortical auditory development continues throughout childhood, and that different facets of auditory processing follow distinct developmental trajectories. SIGNIFICANCE: The present findings improve our understanding of auditory system development in typically-developing children, opening the door for future investigations of disordered sound processing in clinical populations.

Rhythm, reading, and sound processing in the brain in preschool children.

A child's success in school relies on their ability to quickly grasp language and reading skills, the foundations of which are acquired even before entering a formal classroom setting. Previous studies in preschoolers have begun to establish relationships linking beat synchronization, preliteracy skills, and auditory processing. Beat synchronization involves the integration of sensorimotor systems with auditory and cognitive circuits and, therefore calls on many of the same neural networks as language. Using a drumming task, we analyzed the relationship between children's ability to maintain an isochronous beat with preliteracy skills and frequency following responses (FFRs) in over 150 preschoolers. We show that preschoolers who performed well on the beat synchronization task outscored their peers on all preliteracy measures and had more robust FFRs. Furthermore, the good synchronizers experienced less degradation of certain FFR measures when listening in noise. Together, our results are consistent with the view that rhythm, preliteracy, and auditory processing are interconnected during early childhood.