University of Tennessee Health Science Center
UTHSC Digital Commons (University of Tennessee Health Science Center)Not a member yet
1172 research outputs found
Sort by
T Cell Responsiveness Through the Ages: Functional Diversity of Age-Dependent Antiviral Responses
Get PDFAn organism’s age impacts its susceptibility to disease, which varies according to the type of insult or causal pathogen. Much work remains to delineate these complexities, especially within younger individuals. Indeed, pediatric disease-driven immunity is less characterized than adult and aging populations due to two main factors: 1) descriptions through multiple stages of development are required, as the immune system undergoes massive changes from gestation through the end of adolescence, and 2) the complex nature of pediatric research decreases the availability of robust and comprehensive studies. Importantly, studying the immune system in relation to age requires a foundational knowledge within adult individuals to adequately assess the unique characteristics of the developing and aged systems. This body of work contributes to the field of age-dependent immunity via the study of repair-associated T cell subsets in pediatric acute respiratory distress syndrome (pARDS), γδ T cells in murine cytomegalovirus (MCMV), and multiple immune mediators and cell populations in adult severe influenza infection. Single-cell RNA sequencing of tracheal aspirate cells from pediatric subjects experiencing acute respiratory failure (ARF) showed that distinct T cell subsets within the lower respiratory tract exhibited transcriptional similarity, termed functional redundancy. This similarity was repair-associated, and a defining gene of the transcriptional profile was amphiregulin (AREG). When quantified, T cells from subjects with a viral lower respiratory tract infection (LRTI) that did not progress to moderate or severe pARDS had significantly elevated repair scores. This was reflected within tissue resident memory (TRM) CD8 T cells, activated regulatory CD4 T cells (Tregs), and activated AREG+ γδ T cells. The repair profile was then applied across publicly available datasets spanning ages, tissue types, etiologies, and severities, and functional redundancy was only observed within the same three subsets of tracheal aspirate T cells from healthy pediatric subjects. Additional validation confirmed that nasal wash supernatant proteins from the repair profile were inversely correlated with age. Collectively, these findings indicated that T cells within the respiratory tract exhibited functional redundancy linked to tissue repair in an age-dependent manner, and that this redundancy was associated with decreased disease severity. Results from mouse models of MCMV infection demonstrated that the functionality of γδ T cells is shaped by infection in an age-specific manner. γδ T cells from neonates infected with MCMV underwent a shift in cytokine production that was absent in acutely infected adult, aged, and geriatric mice. Neonatal infection also affected the γδ T cell receptor (TCR) repertoire by modulating the hierarchy of segment usage. Single-cell RNA sequencing with paired TCR repertoire data from the lungs showed that both age and MCMV infection impacted γδ T cells in a manner determined by age of viral exposure, viral state, and age of the mouse at endpoint characterization. These data highlight age-associated functionality of γδ T cells in MCMV infection, and the role that age of exposure plays in shaping γδ T cell immunity. Lastly, a cohort of oseltamivir-treated adults with severe influenza infection were utilized to address 3 questions: 1) What is the relationship between patient risk and severity scores throughout severe influenza infection? 2) What immunological features underlay severe influenza infection? 3) What immune biomarkers are predictive of infection severity and clinical outcome? First, assessment of the relationship between risk and severity scores showed increased correlation between metrics that incorporated supplemental oxygen usage, as well as those which were less subjective in nature. No correlations were observed for intake risk metrics or subjective severity scoring. Second, a decrease in protection-associated cytokines and innate immune mediators was observed over the course of severe infection across all individuals. Additionally, subjects with heightened severity exhibited decreased upper respiratory and peripheral pro-inflammatory and pleiotropic cytokines at study day 0, decreased T cells spanning naive and memory phenotypes at study days 0, 3, and 28, and decreased peripheral eotaxin at study day 28. Third, peripheral myeloid analytes were positively associated with severity based on intake vitals, while cytotoxic natural killer T (NKT) cells were negatively associated. Multiple circulating and upper respiratory cytokines were predictive of peak infection severity, as was the frequency of circulating eosinophils. For correlative analyses, age was included in all linear regression modeling, since the study included both adult and elderly individuals. In conclusion, these data established the presence of functionally redundant pediatric T cells in the airway, identified age-associated features of γδ T cells in MCMV-infected lungs, and laid the foundation for studies of severe influenza infection in antiviral-treated individuals across different ages. The unique functions of pediatric T cells in this body of work widen the scope of future age-associated immune studies, which will impact study design, interpretation, and subsequent therapeutic development
The Role of TCR Engagement Strength in Antitumor CD8 T Cell Exhaustion
Get PDFDurability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8 T cells (Tpex). Tpex serve as a source for the pool of effector T cells that tend to have a short lifespan or eventually become dysfunctional in uncleared tumors. In contrast to the short-lived feature of their daughter cells, Tpex are able to preserve their quantity and developmental potential through a process of self-renewal. Previous research has demonstrated that Tpex can even self-renew in the absence of their cognate antigen. However, it remains unknown how T cell receptor (TCR) engagement impacts the self-renewal capacity of Tpex in settings of continued antigen exposure. Given that many cancer cells lack antigens capable of effectively engaging with TCRs, it is important to understand whether and how TCR engagement strength regulates the preservation of Tpex and their terminal differentiation during tumor progression. To investigate this, I established multiple murine tumor models, including Lewis lung carcinoma, which elicit an optimal or attenuated TCR signal in CD8 T cells. Longitu- dinal phenotyping and single-cell transcriptomics of tumor-specific T cells revealed that formation and maintenance of the Tpex reservoir in tumor-draining lymph nodes (tdLN) is dependent on optimal TCR engagement. Despite the generation of central memory-like T cells in tdLN under suboptimal priming, replenishment of tumor-infiltrating Tpex is abrogated. Moreover, adoptive transfer of optimally primed Tpex into a tumor setting with attenuated TCR stimulation significantly accelerates their terminal differentiation. This TCR-reinforced Tpex development and self-renewal is coupled to proximal position- ing to dendritic cell niches and epigenetic imprinting that involves increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, my dissertation work reveals a previously unappreciated and coun- terintuitive role of TCR stimulation in preserving Tpex and highlights TCR-dependent self-renewal of Tpex during tumor progression. These results provide fundamental insight into T cell exhaustion and have important implications for the development of cancer vaccines that target tumor-epitopes with varying TCR binding avidities
Investigating Potential Quantitative Trait Loci for Susceptibility to Experimental Autoimmune Encephalomyelitis in the BXD Family of Mice
Get PDFMultiple Sclerosis is an autoimmune inflammatory condition that causes disability, axonal damage in the central nervous system, and eventual paralysis. One of the main risk factors for developing MS is genetics, with recent studies identifying multiple risk alleles associated the major histocompatibility complex. By utilizing the BXD family of mice, we investigated genetic factors that affect a BXD strain’s susceptibility to EAE, an inducible disease model for MS. We induced EAE in several BXD mice strains via an emulsion of complete Freund’s adjuvant and MOG35-55, and then measured disease severity in each strain. From there, we measured incidence rate of EAE, average peak clinical score, average day of disease onset, average length of acute onset, and average end clinical score. Afterwards, we tested EAE severity in the BXD43 mouse by identifying changes in immune cell populations in the spinal cord, changes in cytokines and chemokines, and distribution of the Fc multimer drug M019. Out of 16 strains tested, we identified 6 BXD strains susceptible to developing EAE, and found suggestive evidence of QTLs on chromosomes 5 and 11. We also found that the BXD43 strain expressed an extreme phenotype, categorized by increased immune cell populations in the spinal cord comparable to the B6 EAE model with pertussis toxin. These results suggest the potential for QTLs to exist on chromosomes 5 and 11, though more BXD strains need to be tested. Additionally, the BXD43 strain shows promise as an extreme phenotype model for EAE, which may serve as an effective model for primary progressive multiple sclerosis
Androgen Receptor: A Complex Therapeutic Target in Breast Cancer
Get PDFBreast cancer is classified based on the expression of three markers estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor (HER2). Breast cancers that express these targets are classified as hormone receptor (HR) positive breast cancer and the tumors that lack the expression of these markers are classified as triple negative breast cancer (TNBC). Though HR-positive breast cancer is treated with hormonal and cyclin-dependent kinase 4/6 targeted therapies, the cancer relapses and becomes resistant to the treatment options. Androgen receptor (AR) that is expressed in over 90\% of ER-positive breast cancer and in 20\% of TNBC is a pharmacologically targetable tumor suppressor in ER-positive breast cancer and a targetable oncogene in TNBC (luminal AR TNBC (LAR TNBC)). Here we show that the efficacy of AR agonists in ER-positive breast cancer depends on the cellular elasticity wherein AR agonists promote a more luminal state as a consequence of inhibiting oncogenic pathways. Sustained treatment of ER-positive breast cancer in vitro and in vivo with AR agonists results in rearrangement of AR, ER, and FOXA1 cistromes, transformation of tumor suppressor AR into oncogenic AR, and activation of the JAK/STAT pathway, all culminating in lineage plasticity and resistance. This unique shift of AR into an oncogene (previously unreported for the tumor suppressor class) and increase in JAK/STAT signaling switches the tumor cells from luminal ER-positive breast cancer to an intermediate ER/AR-positive basal subtype, whose growth was inhibited by AR antagonists or JAK/STAT inhibitor. Treatment with a JAK inhibitor also re-sensitizes the resistant cells to AR agonists.
While we show that AR can shift from tumor suppressor to an oncogene in ER-positive breast cancer, in TNBC we identified that the tumors not only express full-length AR (AR-FL) at a much higher rate (~80\%) than previously reported, but also express AR splice variants (AR-SVs) (~20\%), subclassifying the LAR-TNBC subtype into LAR-FL, LAR-AR-SV, or dual positive. Higher AR and AR-SV expression and corresponding aggressive phenotypes were observed predominantly in specimens obtained from African American women. RNA sequencing of LAR TNBC specimens indicates an enrichment of hallmark interferon, JAK/STAT, and androgen signaling pathways, which were exclusive to AR-expressing epithelial cancer cells as demonstrated by spatial genomics. LAR and LAR-AR-SV TNBC cell proliferation, orthotopic cell line and patient-derived xenograft, and patient-derived tumor explants growth were inhibited by AR N-terminal domain (NTD)-binding selective AR degrader (SARD) that irreversibly inhibits AR or by the JAK inhibitor ruxolitinib. Subsequent biochemical analysis suggests that STAT1 is an AR coactivator, and SARD or ruxolitinib blocks this coactivation.
Collectively, we identified that AR has multifaceted role in breast cancer and co-expression of JAK/STAT pathway defines the function of AR as a tumor suppressor or oncogene, providing a mechanism of action for AR in breast cancer and also a roadmap for therapeutic development targeting the two important pathways
Transmission Competence of B. burgdorferi Infected Ixodes Ticks and Development of an OspC-Based Lyme Disease Vaccine
Get PDFIntroduction. Lyme disease, otherwise called Lyme borreliosis, is a vector-borne infectious disease caused by the spirochete Borrelia burgdorferi (Bb). Studying the increase in overall Lyme disease incidence requires understanding the role of the vector Ixodes scapularis (I. scapularis) as the agent that carries the spirochete which is important to limit the occurrence of Lyme disease. Once we understand the vector-pathogen response, it also becomes important to determine the remedies for Lyme disease. Lyme disease can be treated with antibiotics if detected early, but the major obstacle lies in the early detection process. Therefore, it is important to investigate alternative preventive measures. Although vaccines could serve that purpose, there are no vaccines currently available for Lyme disease in humans. A few Outer surface protein A (OspA) based compositions are currently undergoing clinical trials for human use. Outer surface protein C (OspC) is an alternative in the same line because it induces a significant antibody response and provides strain-specific protection after the tick challenge. However, due to OspC heterogeneity, there are limitations to using OspC as a broad-spectrum vaccine candidate. To this end, our lab designed a cocktail vaccine (OspCCt) comprised of 8 different OspC types selected for their ability to disseminate to target human organs. OspA and OspC are two important outer surface proteins of Bb, and they are genetically dissimilar. Despite the antigenic differences, we observed cross-reactivity between the OspC antigen and OspA serum antibodies. Studies have shown OspA to be an effective transmission-blocking vaccine. Therefore it is also important to investigate the transmission-blocking properties of the OspCCt vaccine observed in the ticks recovered from infected and vaccinated mice. Objective. Our first goal is to investigate whether I. scapularis nymphs kept in a prolonged questing state under optimal environmental conditions are fit to fulfill their transmission role in the enzootic cycle of Bb. We wanted to check for differences in Bb infection prevalence between the questing (actively moving and looking for hosts on which to feed) and diapausal (in suspended development) nymphs over a year. Our second objective is to design a vaccine candidate utilizing OspC. Finally, we analyzed whether there is any cross-reactivity between OspC and OspA, to define the function of OspC alone in blocking Bb transmission. Research Design. To understand the transmission competence of I. scapularis during prolonged questing, we first generated infected I. scapularis nymphs by allowing larvae to feed on infected mice. Firstly, the mice were infected through sub-cutaneous needle inoculation with cultured Bb (105) recovered from frozen stock. After needle inoculation, it takes three weeks for Bb to disseminate in naive mice fully. Then, I. scapularis larvae are placed on the infected mice and allowed to engorge and fall off naturally fully. Infected engorged larvae are collected and kept in glass vials for six weeks to allow them to molt into nymphs. In another six weeks after molting, the infected I. scapularis nymphs are ready for their nymphal blood meal. During this study, we analyzed differences in Bb infection prevalence between questing and diapausal nymphs after six weeks post-molting (prime questing). Additionally, we checked for differences in the infection prevalence of these nymphs when kept in a prolonged questing state for over 12 months. Lastly, we analyzed the ability of nymphal ticks to transmit Bb into naive mice at certain time points during the prolonged questing phase. Our second objective was to determine the efficacy of our OspCCt vaccine. To design this vaccine, we utilized eight full-length OspC recombinant proteins predominantly expressed by Bb when disseminated to secondary sites in humans (blood and cerebrospinal fluid). The cocktail vaccine is comprised of OspC types A, B, C, D, H, I, K, and N, in equal concentrations, and 50 µg of the cocktail was delivered subcutaneously. The vaccination schedule includes a prime vaccination and two boosts. The efficacy of the OspCCt was determined by analyzing serum antibodies against Bb and by checking Bb dissemination in different sites of vaccinated mice after the tick challenge. Serology was also performed to investigate the source of cross-reactivity between OspA and OspC. Results. Regarding our first objective, we determined that Bb-infected unfed I. scapularis nymphs survived for a year in prolonged questing under optimal environmental conditions in the laboratory and maintained a nymphal infection prevalence sufficient to effectively fulfill the enzootic cycle of Bb. In pursuit of our second objective, we confirmed the absence of Bb in ticks recovered from 55% of the mice vaccinated with rOspCCt, suggesting a partial transmission-blocking mechanism. The cocktail vaccine also generated antigen-specific antibodies in serum and partially protected the tick-challenged mice from borrelial dissemination. Additionally, serum from the challenged mice (55%) was shown to contain effective neutralizing antibodies against Bb. In addition, our study provided ample evidence that antibodies to OspC do not cross-react directly with OspA and vice versa, which further validates the transmission-blocking function of OspC independently of OspA. Conclusion. We investigated the transmission competence of I. scapularis for an extended period, and this study raises important questions regarding the prolonged survival of Bb-infected host-seeking nymphal I. scapularis ticks. Infected ticks can potentially increase the risk of Lyme disease if environmental conditions such as temperature and humidity become favorable to the enzootic cycle of Bb in regions currently classified as non-endemic. The 55% efficacy observed in the OspCCt-derived vaccine can be explained by the difference between OspC types present in the cocktail and those present in the ticks used for the challenge. Although OspC remains a potential vaccine candidate for Lyme disease, future studies must account for additional OspC types and challenges, including field-caught infected ticks. Our study also shows that OspA and OspC are two entirely different antigens with no antigen-antibody cross-reactivity. Antibodies to OspC alone are responsible for the observed transmission-blocking mechanism, independently of OspA
Teach-Back Method to Reduce CHF Readmissions: A Scoping Review
Get PDFPurpose/Background
The purpose of this scoping review is to evaluate the effectiveness of the teach-back method on education as it relates to congestive heart failure readmission rates. Congestive heart failure (CHF) is the most common cause of hospitalizations among those 65 years and older in the United States. CHF readmission rates in Tennessee are higher than the already elevated national average. The current literature suggests a need to reduce 30-day readmissions, improve patient outcomes, and enhance self-efficacy in patients with CHF. The research proposes a correlation between high readmission rates and poor knowledge retention of patients with CHF, but small sample sizes and poor follow-up have interfered with accurate results. We reviewed the existing research regarding the impact of teach-back education on readmission rates and associated outcomes in patients with CHF.
Methods
The articles included were written in the English language, issued in medical or nursing journals, published within the past decade, involved human participants, consisted of an adult patient population (classified as by age \u3e 18 years), encompassed a diagnosis of heart failure, used the teach-back method, and evaluated the outcome of 30-day readmissions. Articles included in this review are systematic reviews/meta-analyses, randomized control trials, case-control/cohort studies, and qualitative/descriptive studies.
The databases were searched from October 2020 to October 2022: CINAHL, Cochrane, JAMA, Medline, and Ovid.
Results
Ten articles published between 2013 and 2022 evaluated the use of teach-back education for patients diagnosed with heart failure in the acute care setting. Teach-back reduced 30-day readmissions in 9/10 articles (unchanged in one), increased patient knowledge of heart failure among all the articles, improved self-management capability (9/10), and promoted treatment adherence (7/10; not examined in 2).
Implications for Nursing Practice
When educating patients with CHF, incorporating the teach-back method has proven to reduce 30-day hospital readmissions and improve patient outcomes
Medication-Assisted Therapy and First Episode Psychosis: Evaluating Treatment and Readmission Rates: A Scoping Review
Get PDFPurpose/Background:
There is limited research aimed at addressing the reoccurrence of admission rates for first-episode psychosis. Research shows that early interventions for first-episode psychosis lead to remissions and prevention of relapses. Research also estimates that approximately one-half of first-episode clients have a history of cannabis abuse or dependence and one-third have a current cannabis use disorder (Wisdom et al., 2011). This study looks to determine whether Medication-assisted therapy (MAT) impacts readmission rates for patients who have substance use disorder and first-episode psychosis within six months of discharge.
Methods:
A comprehensive literature search was conducted using several electronic databases, including PubMed, Cochrane Library, and CINAHL. The search was limited to articles published in English between 2011 and 2021 using The University of Tennessee Health Science Center (UTHSC) database. All articles utilized human subjects who met diagnostic criteria for psychosis and were able to consent to treatment. Key words included: medication-assisted therapy, first episode psychosis, psychosis, substance use disorders, and others. Eleven articles were initially found that met the criteria. After a rapid critical appraisal and in-depth discussion of the articles, the remaining nine were chosen for the final selection.
Findings:
The key areas assessed in the articles include various types of MAT, and substance use disorders including alcohol use, cannabis, and opiate use disorders. The results of the studies showed that the use of MAT in individuals with first-episode psychosis improved treatment outcomes and reduced readmission rates.
Implications for Nursing Practice:
The results of the scoping review suggest that MAT may be effective in reducing readmission rates and improving treatment outcomes for those with first-episode psychosis and comorbid substance use disorder. However, more research is needed to determine specific types of MAT, dosage, and duration of MAT in this specific patient population
Design and Synthesis of Novel Small Molecule Drugs for the Treatment of Cancer and Osteoporosis
Get PDFCancer and osteoporosis are two commonly diagnosed disease around the world which poses major health threat. In this thesis, we provide the background information to two types of cancers, namely ovarian cancer and liver cancer, as well as osteoporosis, and our approach for the treatment of the diseases. In chapter one, we discussed the background information about the diseases. The cause and the current treatment options are discussed, providing the basis for the chapters written later. In chapter two, we focused on the treatment of hepatocellular carcinoma. To construct the drug, we utilized a technique called small molecule drug conjugate, which combines the potency of the payload and the selectivity of the targeting moiety. We designed the conjugate using a potent tubulin inhibitor, veru-111, a targeting moiety reported in the literature, and a glutathione responsive linker, and then, successfully synthesized the compound, waiting for further biological testing. In chapter three, we described our findings on the compound HL142 for the treatment of ovarian cancer. Epithelial to mesenchymal transition is a central mechanism related to ovarian cancer metastasis and chemoresistance, and the protein, ASAP1, is essential for the process. By searching the literature, we found a compound, luminacin D, which may inhibit the protein. Thus, HL142, the analogue of which, was tested in the ovarian cancer model in vitro and in vivo. The results suggested HL142 as a potent compound for inhibiting ovarian cancer tumor growth, metastasis and invasion, making it a good starting point for further modifications. In chapter four, we described the structure based drug design on the compound, MS, which was previously identified in the in silico screening. The SAR of which was extensively studied, and several compounds were identified to have better potency than the lead compound in the in vitro study, which might be further modified into drugs treating osteoporosis. In conclusion, using different approaches, we successfully found numerous com- pounds for the treatment of different diseases, which may provide a solid base for the development of brand new drugs
Matrix Gene Splicing and Emergence of Highly Pathogenic Avian Influenza
Get PDFHighly pathogenic avian influenza (HPAI) is a continual threat to the commercial poultry industry. In the past 40 years there have been five outbreaks of HPAI in North America. Rapid responses to these outbreaks have been crucial in preventing HPAI from becoming endemic in North America. The three worst outbreaks of HPAI in North America occurred in 1983-84, 2014-15, and 2021-23. The most recent outbreak was the worst North American HPAI outbreak in recorded history and will likely result in endemicity. Here we described the three worst recorded HPAI outbreaks in North America. The first of these outbreaks occurred in 1983-1984 and resulted in culling of almost 17 million chickens, turkeys, and guinea fowl. We demonstrated that the 1980s Pennsylvania linage was unique regarding their M gene splicing. These viruses were capable of producing messenger RNA 4 (mRNA4), which had direct implications in the emergence of virulent viruses from this lineage. The avirulent viruses expressed mRNA4 at high levels. We demonstrated that there was strong selection for virulent viruses with weaker mRNA4 splice donor sites. On at least three separate and independent occasions these viruses decreased their mRNA4 expression. Two of these incidents resulted in the emergence of virulent isolates. We demonstrate that a combination of mutations in the M gene coupled with a single amino acid change point mutation were necessary for these viruses to emerge as virulent. We then compared the two North American HPAI outbreaks from the Asian originating goose/Guangdong (Gs/GD) lineage. This lineage has invaded North America on two separate occasions. In 2014-15 these viruses came from Russia and into Alaska and down the Pacific coast of the United States and reassorted with circulating viruses in wild birds. This outbreak resulted in culling of 50.5 million commercial birds. However, rapid response and stamping out procedures were essential in preventing endemicity. In 2021 viruses from the Gs/GD lineage invaded North America. Similar to the 2014-15 outbreak, these viruses originated from Eurasia, but differed in the flyway used to enter North America. Once in North America these viruses reassorted with circulating influenza A viruses in wild bird populations. In our study we used viruses isolated from wild birds and characterized the genotypes and phenotypes of these emergent reassortant viruses. We demonstrated that after these viruses acquired North American wild bird gene segments, they became neuroinvasive and highly virulent in mammalian animal models. To date, this outbreak has resulted in culling almost 60 million commercial poultry. Our results determined that these viruses, although virulent in mammals, retained mostly avian characteristics. We then assessed the risk of the 2021-23 HPAI outbreak to the poultry industry, wild bird populations, and public health. Current vaccine strategies against emerging HPAI strains requires generating reverse genetics (RG) entirely from complementary DNA (cDNA). One of the more common systems utilizes eight plasmids where the cDNA of all eight viral genomic segments is cloned into the bidirectional expression vector pHW2000. This vector encodes the human RNA polymerase I promoter in the reverse direction and the human cytomegalovirus RNA polymerase II promoter in the forward direction. Additionally, it has a T7 promoter with no functional role in cloning viral RNA or generating reverse genetics viruses. During the cloning process leaky expression of flu transcripts in the transformed bacteria occurs from the cytomegalovirus and T7 promoters. Leaky expression of deleterious transcripts puts mutational pressure on the cDNA insert and has become a widespread problem in the field. Here, we demonstrate that mutating the T7 promoter improves plasmid stability and transformation. Generation of RG candidate vaccine strains are now easier with improved efficacy and decreased leaky bacterial expression. This improved plasmid known as pPW2000 can now be used to clone cDNA of emergent viruses and for increased response times when reassortants or novel HPAI strains emerge in nature and threaten public health
Evaluation of Efferent Unmasking Using Cortical Auditory-Evoked Potentials
Get PDFPurpose. All human beings, regardless of whether they have hearing impairments or not, face difficulties in detecting signals in the presence of background noise. To cope with such situations, people can enhance their performance by either increasing the signal levels or reducing the noise levels, which in turn increases the signal-to-noise ratios (SNRs). SNRs play a crucial role in determining one\u27s speech perception abilities. For instance, if the noise levels are high, individuals may raise their voices or decrease their distance from the source to amplify the signal levels, thereby increasing the SNR. However, in real-life situations, individuals may not be able to control these variables, leading to variations in their ability to detect signals in noise. Such variations may be attributed to differences in the auditory efferent system among individuals. The auditory efferent system can potentially improve SNRs through Medial Olivocochlear Reflex (MOCR)-mediated unmasking, as supported by animal studies. Nevertheless, it is not clear to what extent the efferent system can enhance SNRs in humans. Cortical Auditory Evoked Potentials (CAEPs) can serve as a useful tool to assess the impact of the auditory efferent system on humans, as they are highly sensitive to changes in SNRs.
Methods. Out of the total 50 participants, data from 47 participants were included in the analysis. The primary goal of this study was to investigate the auditory efferent system in humans: aim 1) measures the effect of MOCR activation on CAEPs in response to a tone presented in quiet. A 1-kHz tone at 60 dB SPL was presented to the ipsilateral ear with and without contralateral noise at 60 dB SPL. aim 2) the effect of MOCR activation on CAEPs in response to a tone presented in noise. A 1-kHz tone in noise was presented to the ipsilateral ear at different SNRs (25 dB, 15 dB, and 5 dB). Otoacoustic emissions (OAEs) and tone-detection tests were additionally tested to verify the MOCR effect.
Results. In Aim 1, it was expected that the MOCR effect would decrease SNR, resulting in increased latency and decrease inter-amplitude. However, no noticeable changes in latency and inter-amplitude were observed as a result of the MOCR effect. In Aim 2, it was expected that the MOCR effect would enhance SNR, resulting in decreased latency and increased inter-amplitude. The unmasking effect on latency and inter-amplitude was observed only at specific SNR levels at 5 dB and 15 dB SNR. Furthermore, the correlation between the shift in OAE level and tone-detection level was found to be unrelated in Aim 1. However, in Aim 2, a significant correlation was observed between these shifts at a specific SNR, specifically at 5 dB or 15 dB SNR.
Conclusions. In aim 1 (MOCR effect in a quiet environment), the activation of the MOCR does not significantly affect LLR latency and inter-amplitude. One possible factor that influences these results is the duration of the measurement session, as it may reduce the MOCR effect. Another possibility is that the reduction in cochlear output caused by MOCR activation may be compensated for by central gain. In aim 2 (MOCR effect in noise environment), LLR latency decreases during MOCR activation at 5- and 15-dB SNR, indicating that the efferent system enhances SNR through the MOCR-mediated unmasking effect at the neural level. Specifically, the unmasking effect increases sensitivity to a specific SNR. However, we were unable to identify a relationship between MOCR metrics, pre-neural assay, and behavioral assay. The lack of association in the MOCR analysis may be attributed to the use of different stimuli, diminished MOCR effect over time, and the introduction of high artifacts