Detecting Verbal Auditory Hallucination Among Schizophrenia Patients by Integrating Alternate Auditory Attention Tasks in Contralateral Suppression of Otoacoustic Emissions

Detecting Verbal Auditory Hallucination Among Schizophrenia Patients by Integrating Alternate Auditory Attention Tasks in Contralateral Suppression of Otoacoustic Emissions | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Detecting Verbal Auditory Hallucination Among Schizophrenia Patients by Integrating Alternate Auditory Attention Tasks in Contralateral Suppression of Otoacoustic Emissions Che Muhammad Amir Che Awang, Noor Alaudin Abdul Wahab, Nashrah Maamor, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5163811/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Mar, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Subjective evaluations of verbal auditory hallucinations (VAH) in schizophrenia have limitations; thus, combining them with objective measures like neuroimaging may provide more accurate insights into brain activity during VAH episodes. However, neuroimaging is often costly and time-consuming, prompting the search for alternative methods. This study explores the integration of ALternate AUDItory AttentioN (ALAUDIN©) tasks with Contralateral Suppression of Otoacoustic Emissions (CSOAE) as a rapid and cost-effective approach to detect VAH in schizophrenia patients. A total of 57 healthy controls (HC) and 10 schizophrenia patients; five with active and five with passive VAH; participated. Various contralateral stimuli, including white noise (WN) alone and WN combined with auditory attention tasks, were used to evaluate CSOAE. While no significant differences in suppression were found between the left and right ears across all groups, patients with active VAH demonstrated significantly higher suppression than HC for specific stimuli (CS4). Notably, incorporating ALAUDIN© tasks did not significantly enhance suppression in HC or patients with passive VAH but descriptively increased suppression in those with active VAH. These results suggest that ALAUDIN©-CSOAE may effectively differentiate schizophrenia patients with VAH from healthy individuals, warranting further research with larger sample sizes to validate these findings. Biological sciences/Neuroscience/Auditory system/Cochlea Biological sciences/Neuroscience/Auditory system/Hair cell Biological sciences/Neuroscience/Auditory system/Inner ear Schizophrenia Efferent pathways Otoacoustic emissions Suppression Figures Figure 1 Figure 2 INTRODUCTION Schizophrenia is a multidimensional neuropsychiatric disorder that affects approximately 1% of the global population. Schizophrenia poses significant economic and social challenges to individuals, families, and society as a whole. Verbal auditory hallucinations (VAHs) are among the most distressing symptoms associated with schizophrenia. It is estimated that 60 to 90 percent of people with schizophrenia suffer from VAHs. Despite the fact that the mechanisms underlying these hallucinations remain poorly understood, studies have begun to explore the neurobiological and cognitive aspects of the phenomenon. It has been suggested that disconnection of brain regions such as the temporal lobe and prefrontal cortex may play a role in auditory hallucinations. 1 Understanding VAH is crucial to developing treatment and rehabilitation strategies that address patients' needs and improve their social functioning. For instance, several studies examining neurofeedback training have suggested that individuals suffering from VAH may benefit from this training, since it may help them gain control of their experiences by self-regulating brain activity in related networks. 2 Hence, research on auditory modalities and audiological assessments can further advance our understanding of these phenomena in schizophrenia. Auditory hallucinations are defined as sensory perceptions of hearing in the absence of an external stimulus. Subjective evaluation of auditory hallucinations is typically conducted through clinical interviews and self-report measures such as Auditory Hallucinations Risk Assessment Scale and The Psychotic Symptom Rating Scales. 3,4 It is important to note that the experience of auditory hallucinations is highly individual, and subjectiveevaluation helps clinicians and researchers understand the nature and impact of these hallucinations on an individual's life. While subjective evaluation methods provide valuable insights into the individual experience of auditory hallucinations, they have certain limitations that should be considered. These limitations include, but are not limited to subjectivity and reliability, limited observability, memory recall and response biases, and psychological and emotional biases. 5,6 In the context of an interview, patient reports are highly susceptible to manipulation, making them inconsistent with psychiatrist observations. To overcome these limitations, a thorough evaluation of auditory hallucinations may include both subjective assessments and objective measures like neuroimaging. Objective tests, such as functional Magnetic Resonance Imaging (fMRI), can be used to investigate brain abnormalities, including issues with neural networks and dysconnectivity. 7,8 Although fMRI is non-invasive, it is both very costly and time-consuming. Hence, the current study investigates the potential of integrating ALternate AUDItory AttentioN (ALAUDIN©) tasks with Contralateral Suppression of Otoacoustic Emissions (CSOAE) in detecting auditory hallucinations in schizophrenia patients. Otoacoustic emissions (OAE) is a rapid, relatively cost-effective and objective test to non-invasively measure the micromechanics of cochlea outer hair cells. OAE was introduced by Kemp 9 where he explained how the motility of healthy outer hair cells (OHCs) of the cochlea produces low energy sound pressure which is measured in the outer ear canal. OAE magnitude of at least 6dB above the noise floor reflects healthy and intact outer hair cells. Interestingly, the motility of cochlea OHCs can be suppressed by two efferent auditory pathways, namely caudal and rostral which are located at the lower brainstem and higher auditory centre respectively. The efferent auditory pathway plays an important role in regulating the outer hair cells of the cochlea. 10 The current belief is the caudal section, which consists of medial olivocochlear bundle (MOCB), acts as a contralateral reflex pathway to suppress OHCs of a tested ear with the presence of white noise in the contralateral (non-tested) ear. The efferent MOC did not play a crucial role in changing the micromechanics of outer hair cells in response to auditory attention or behavioral tasks. 11,12 The conclusion is based on the finding that there are no significant changes in the level of noise in the external ear canal, the magnitude of OAE, and the strength of the MOC reflex when normal subjects are given a multi-modality attention task and a range of auditory focus difficulties. For now, white noise has been successfully used as a suppressor in studies related to CSOAE. On the other hand, the role of the rostral section of the efferent auditory pathway is still less understood. The lack of understanding could be due to the anatomical complexity of the pathway which consists of the cortico-olivocochlear bundle (COCB). The COCB communicates with the caudal efferent pathways at the lower brainstem which eventually affect the electromotility of the OHCs. We speculate that to suppress the OHC via the rostral efferent pathway, the contralateral suppressors should have the ability to at least stimulate the auditory cortex. Activation of the auditory cortex would stimulate the rostral which eventually suppresses the cochlea outer hair cells via the caudal pathway. This is consistent with a previous study where electrical stimulation of the auditory cortex can reduce the magnitude of OAE. In fact, our recent study of the effect of contralateral ALAUDIN© tasks suggests the positive effect on healthy normal-hearing adults. 13 Currently, there are no non-invasive, cost-effective, and objective tests that can rapidly detect verbal auditory hallucinations (VAH) in schizophrenia patients. This study, therefore, explores the integration of ALAUDIN© tasks into contralateral suppression otoacoustic emission (CSOAE) testing. This integrated ALAUDIN©-CSOAE approach aims to distinguish schizophrenia patients with VAH from those without it. The development of this method is based on the following concepts: In humans, efferent (top-down) auditory pathways exist alongside afferent pathways. 14 This is anatomically supported by the presence of the medial olivocochlear bundle (MOCB) in the caudal section and the cortico olivocochlear bundle (COCB) in the rostral section of the central auditory system. 15 The caudal section transmits electrical signals from the superior olivary complex (SOC) to its ipsilateral counterpart and partially to its contralateral counterpart. The rostral section is more complex, consisting of nerve fibres that originate in the auditory cortex, synapse with both ipsilateral and contralateral SOC, and ultimately innervate the basal portion of outer hair cells (OHCs). 16 As a result, auditory-related activities in the auditory cortices can indirectly influence the micromechanics of cochlear OHCs. Activities such as auditory attention, which involve active communication between the pre-frontal lobes and auditory cortices, may also affect OHC micromechanics. Activating the auditory cortex engages the efferent pathway, altering the cochlea's micromechanics. Studies have shown that activation of the auditory cortex by electrical stimulation 17 and selective attention 10 can modify the micromechanics of the OHC. Processing auditory information is also associated with prefrontal cortex activity, especially when selective attention is engaged. 18 Some of the problems with this relationship may affect sound processing in the auditory cortex, which in turn may affect efferent pathways and the OHC. In schizophrenia patients, the disconnectivity among brain regions, i.e. pre-frontal lobe and auditory cortex, causes the auditory cortex to function abnormally 19,20 and leads to auditory hallucinations. 21 By measuring changes in OHC micromechanics, it is possible to assess the integrity of the auditory efferent pathways. To achieve this, otoacoustic emission (OAE) amplitudes must be recorded both in the absence and presence of contralateral stimulation. 22 In an intact auditory pathway, a contralateral stimulus reduces OAE amplitude. Contralateral suppression is generally defined as the positive difference in OAE amplitude with and without the presence of contralateral stimulation, such as noise. The normal range of contralateral suppression is reported to be between 1.0 to 3.0dB when white noise is used as a stimulus. 23 However, in the CSOAE routine, white noise is believed to activate only the caudal section, whereas auditory attention tasks are thought to activate the rostral section. A previous study found that schizophrenia patients exhibit higher suppression values compared to normal individuals, suggesting hyperactivity in the efferent pathway, particularly due to the automatic functioning of the auditory cortex. 24 Another study reported no significant difference in CSOAE values between schizophrenia patients and normal individuals. 25 However, these studies did not account for the effect of VAH in their subject selection criteria. Therefore, the current study aims to determine the effects of VAH on the efferent pathways by applying the Integrated ALAUDIN©-CSOAE. In addition to white noise (WN), the ALAUDIN© tasks are designed to optimize the subjects’ auditory attention, thereby activating the rostral section as much as possible. This involves using WN along with tone, WN along with speech, or WN along with both tone and speech. Given the potential dysconnectivity in cortical pathways, this study hypothesizes that there will be significant differences in CSOAE values between schizophrenia patients with and without VAH. If significant differences are found, this test could potentially be used in the future as an objective support tool for detecting hallucinations in a clinical setting. RESULTS Sociodemographic data Table 1 outlines the demographic characteristics of the participants included in the study analysis. The normal healthy control group consisted of 57 individuals, with 35 males (61%) and 22 females (39%). In this group, 52 right ears (48%) and 57 left ears (52%) were considered for the study. The S AC group comprised 5 individuals, with 2 males (40%) and 3 females (60%). For this group, both left and right ears were equally represented, with 5 ears (50%) each. The S PA group included 5 male patients exclusively, with 4 left ears (44%) and 5 right ears (66%) analysed. Table 1. Demographic data of subjects Subjects Ear Gender Total Percentage (%) Right Left Male Female Group HC 52 57 35 22 57 85.08 S AC 5 5 2 3 5 7.46 S PA 4 5 5 0 5 7.46 HC = healthy control; S AC = schizophrenia with active hallucination; S PA = schizophrenia with passive hallucination. TEOAE Suppression between ears across groups Table 2 presents a comparison of mean TEOAE suppression between ears across different groups. In the HC group, there was no statistically significant difference in TEOAE suppression between the left and right ears for all CS (p>0.05). However, the mean TEOAE suppression in the left ear tended to be higher compared to the right ear for each CS. Table 2 . Comparison of mean suppression between ears across groups Contralateral Suppressors HC S AC S PA RE LE p* value RE LE p* value RE LE p* value CS1 1.408 1.632 0.377 3.200 -0.820 3.200 2.725 2.620 0.982 CS2 1.394 1.596 0.516 2.620 2.440 2.620 2.350 0.840 0.705 CS3 1.400 1.623 0.821 1.660 1.960 1.660 -0.500 3.220 0.328 CS4 1.156 1.332 0.559 2.040 4.820 2.040 3.625 2.140 0.665 HC: healthy control, S AC : Schizophrenia with active hallucination, S PA : schizophrenia with passive hallucination; CS1: Stimulus 1; CS2: Stimulus 2; CS3: Stimulus 3; CS4: Stimulus 4. Similarly, in the S AC group, there was no statistically significant difference in TEOAE suppression between the left and right ears for all CS (p>0.05). However, the mean suppression patterns varied inconsistently between ears with different CS. In the S PA group, there was no statistically significant difference in TEOAE suppression between the left and right ear for all CS (p > 0.05). However, the mean suppression was mostly higher in the right ear than in the left ear, except in CS 3. TEOAE suppression by group for each suppressor Figure 1 represents the mean of TEOAE suppression measured across groups for each CS. Combining data from both ears for each group, since there were no significant differences between them, revealed no statistically significant difference in suppression between the groups when using CS1, CS2 and CS3 (p>0.05). However, when using CS4, the difference became statistically significant, with an F value of (2.125) = 5.853 and p=0.004. Moreover, suppression was found to be larger in the S AC group (M=3.4, SD=4.67) compared to the HC group (M=1.2, SD=1.56), showing a mean difference of 2.18 with a 95% confidence interval of [0.42, 3.95], which was statistically significant (p=0.011). TEOAE suppression by suppressors for each group Figure 2 shows the mean TEOAE suppression measured across suppressors for each group. Across all groups, using different CS did not result in any statistically significant changes in TEOAE suppression (p>0.05). However, in the S AC group, using suppressors CS2, CS3, and CS4 (which contain ALAUDIN © tasks) descriptively showed larger suppression compared to suppressor S1, which does not include a task (Figure 2). DISCUSSION In this study, we explored a novel approach which is integrating ALAUDIN© tasks with Contralateral Suppression of Otoacoustic Emissions (CSOAE), to detect verbal auditory hallucinations (VAH) in schizophrenia patients. This research is based on two main premises. First, it addresses the limitations of routine subjective (i.e. questionnaires) and objective methods (i.e. fMRI) in identifying VAH. However, it is important to emphasize that the Integrated ALAUDIN©-CSOAE approach is intended to complement rather than replace these existing methods, offering advantages in terms of time, objectivity, non-invasiveness, and cost-effectiveness. Second, the study is motivated by theories of brain dysconnectivity 21 and interhemispheric miscommunication 26 in explaining VAH, which are attributed to the automatic activation of the auditory cortex. These theories led us to investigate how complex auditory attention tasks might impact the rostral and caudal efferent auditory pathways and, consequently, the micromechanics of cochlear outer hair cells (OHC). The communication between prefrontal areas and auditory cortices plays a crucial role in attention to auditory stimuli, suggesting that challenging auditory attention tasks could have significant implications and open new avenues for future research. As suppression values between ears across all groups showed no significant difference, we combined the values between ears for each group. The results revealed significant differences of TEOAE suppression between groups by using CS4, but not for another CS. Furthermore, post hoc test revealed significant differences in suppression between S AC and HC groups. Interestingly, there was no significant difference in suppression between schizophrenia patients with passive hallucinations (S PA ) with either S AC or HC. These findings suggest three significant implications. First, by integrating ALAUDIN© task into CSOAE, which engage auditory attention, we can provide added value to routine CSOAE in assessing the intactness of the efferent auditory pathway, specifically among patients with schizophrenia. Secondly, our findings support previous literatures on automated activation of the auditory cortex during active hallucinations. This causes hyperactivity of the efferent auditory pathways that, in turn, leads to large suppression of OAE. Third, when engaging in an auditory task that requires understanding speech over a long duration, the primary factor in successfully completing such tasks is listening effort which is derived from cognitive ability. 27,28 However, individuals with schizophrenia often experience deficits in cognitive functions, including temporal processing, which is essential for understanding speech. 29 Hence, the study argues that effort required for individuals with schizophrenia to perform auditory tasks is significantly higher than that of people without the condition. This increased effort likely results in heightened activity in the auditory cortex, which may be more pronounced in schizophrenia patients compared to the control group. Although the precise nature of the relationship between listening effort and auditory cortex activation in schizophrenia patients is not yet fully understood, this connection warrants further investigation. Understanding this relationship could provide insights into the neural mechanisms underlying auditory processing deficits in schizophrenia and help inform more effective therapeutic approaches. The significantly larger suppression with CS4 in S AC compared to HC aligns with previous research, supporting the hyperactivity theory, which suggests that individuals with schizophrenia especially experience VAH exhibit higher levels of OAE suppression compared to normal subjects due to increased activity in the auditory cortex. 24 Moreover, the observation of descriptively larger suppression in S AC compared to S PA lend further credence to the notion that auditory hallucinations may influence the micro-mechanics of outer hair cells, possibly due to dysconnectivity in the brain 15,30 which finally generate auto activation of auditory cortex. This dysconnectivity, particularly affecting the temporo-prefrontal neuronal circuit, may involve deficits in corollary discharge, which normally suppresses activities in the auditory cortex, thereby reducing stimulation of the efferent pathway. 31 Furthermore, alterations in GABA production disrupt the delicate balance of neurotransmitters in the auditory system, leading to an increase in acetylcholine release. This excess acetylcholine triggers hypersensitivity in the outer hair cells, culminating in hyperpolarization and reduced responsiveness to auditory stimuli, ultimately contributing to diminished OAE amplitudes. These findings offer new insights into the potential use of OAE suppression with auditory attention tasks for differentiating between schizophrenia patients with and without hallucinations and normal individuals. Hence, we hypothesize that introducing auditory attention tasks, particularly those that are more challenging, to individuals with disrupted brain area communication will enhance or trigger increased neural firing in the associated brain regions. This increased neural activity may ultimately result in hyperactivity of the efferent pathways. The observations of suppression in S PA could be explained by considering the group as an overlapping population between HC and S AC . In other words, the condition experienced by S PA may represent a transitional phase between HC and S AC . The overlap could indicate that S PA is shifting to either normal or abnormal efferent auditory processing which is influenced by neurochemical stability (i.e. not experiencing VAH) or imbalances (experiencing VAH), in particular the dopamine and glutamate systems, in S PA . As a result, neural activity and communication may be affected, possibly contributing to the overlap observed between S PA and HC or S AC . Additionally, dysconnectivity between cortical regions, at least in the auditory-attention area, and cortical-subcortical functional connectivity have likely improved. Furthermore, improved GABAergic levels may also affect the efferent auditory pathway, leading to a more functional auditory pathway close to normal. Persistent intake and maintenance of atypical antipsychotic are believed may reduce the acute symptoms especially VAH. 32 Hence, it is crucial to consider the classification of patients into S AC and S PA categories. Even though S PA patients are categorized as not experiencing hallucinations, abnormalities may still be present in these individuals. Additionally, the classification of passive hallucination may overlook instances where subtle hallucinations may occur intermittently, potentially leading to non-significant findings. Our findings indicate a greater suppression in the left ear compared to the right ear in the HC group across all CS, aligning with observations from other studies. 24 However, this difference between ears is not statistically significant. This may be attributed to the compromised function between the left and right hemispheres in healthy individuals, which supports their role in auditory processing. 33 This is further supported by the normal function of NMDAR (N-methyl-D-aspartate receptor) in HC, which facilitates intact inter-hemispheric and inter-regional brain communication, particularly between prefrontal and auditory brain areas. 26 Such functionality ensures balanced neurochemical processes and intact excitatory/inhibitory efferent function. Additionally, Gehmacher, et al. 34 propose that an unknown, yet crucial, mutual compensation mechanism between cortical and OHC modulation results in an insignificant difference in MOC reflexes measured with various contralateral auditory suppressors. Collectively, these factors suggest the lack of a significant difference in TEOAE suppression between ears in HC subjects. In both the S AC and S PA groups, our study also did not find a significant difference in suppression between ears, suggesting a lack of asymmetry, similar to the findings of Veuillet and colleagues 25 , who used an equivalent equation technique to determine MOC function. Although the suggestion aligns, discussing the differences in approaches between the studies remains valuable. Unlike Veuillet et al. 25 , the current study employed auditory attention tasks for the subjects. We propose that, beyond the absence of a right ear advantage (REA) in schizophrenia patients, the observed lack of asymmetry may also be linked to the disrupted function of NMDAR receptors in these patients. NMDAR dysfunction results in miscommunication between hemispheres, which is compensated by an increased release of glutamate from the frontal and auditory cortex. This compensation may account for the overall differences observed between schizophrenia patients and healthy controls, but not for the inter-ear differences within the schizophrenia group. However, other studies argued that individuals with schizophrenia tend to exhibit asymmetry of suppression between ears. Hemispheric imbalances were reported in individuals with schizophrenia, particularly those experiencing auditory hallucinations. 35 This imbalance may be attributed to a greater regional cerebral blood flow (rCBF) in the right temporal lobe compared to the left, resulting in heightened neuronal activity in the right temporal lobe. 36 This increased activity may specifically affect the efferent auditory pathway, leading to greater suppression observed in the left outer hair cells (OHCs). However, it's essential to note that these findings do not necessarily imply functional decline in the left temporal lobe. Instead, they raise intriguing questions about the reasons behind the heightened blood flow and activity in the right temporal lobe, potentially leading to overactivity in this region. Furthermore, reports of decreased volume mass in the left temporal lobe, 37,38 add complexity to our understanding, suggesting that lesions may manifest differently among schizophrenia patients. Although there are some discrepancies between the current study and previous research, such as the classification of schizophrenia patients based on active and passive hallucinations, and the small sample size, these variations may have influenced the statistical analyses. A larger sample size in each group could potentially yield more significant differences between the ears, enhancing our understanding of auditory processing abnormalities in schizophrenia. CONCLUSION In summary, the integration of ALAUDIN©-CSOAE is potential in distinguishing individuals with schizophrenia experiencing active auditory hallucinations as they exhibit larger suppression compared to others. This observation is likely due to dysconnectivity leading to hyperactivity in the efferent auditory pathway. Additionally, the more challenging attention tasks, as evidenced by CS4, appears to impact schizophrenia with hallucinations more by significantly increasing suppression values compared to HC group. Lastly, to bolster confidence in this diagnostic tool, further studies with larger sample sizes are necessary. Additionally, assessing the accuracy of this test is vital and could pave the way for an objective, rapid, non-invasive, and cost-effective diagnostic tool for identifying patients with auditory hallucinations. METHODS Subjects The study involved 57 healthy controls (HC) and 10 individuals diagnosed with schizophrenia, aged between 18 and 40 years. Among the schizophrenia patients, five were experiencing active auditory hallucinations (S AC ), while another five were experiencing passive auditory hallucinations (S PA ). Auditory hallucinations that occurred within the previous two weeks, including the day of evaluation, were considered active auditory hallucinations (AH). Passive auditory hallucinations are those in which the participant has not experienced auditory hallucinations for at least two weeks, including the day of the evaluation. All schizophrenia patients were being treated with atypical antipsychotic medications. Importantly, none of the participants, whether healthy or diagnosed with schizophrenia, reported difficulty understanding conversations in either quiet or noisy environments. Additionally, none of them reported having ear disorders, tinnitus, or prolonged exposure to loud noises. The study received ethical approval from the Human Ethics Committee of UKM (JEP-2022-068). This study was performed following the guidelines by Human Ethics Committee of UKM and informed consent was obtained from all subjects. Contralateral suppressors of TEAOEs Instrumentation and stimulus . Audacity version 3.2.1, a multi-track audio editor and recorder for computers, was used for recording, editing, and generating contralateral suppressors (CS). A Sound Pro 1/3 Octave S/N BFL120002 sound level meter equipped with a 2cc coupler was used to calibrate each of the four CS listed below. In addition, these CS displayed high test-retest reliability. 13 1) CS 1 (White noise only) White noise (WN) calibrated at 75dB SPL for one minute. 2) CS 2 (WN + ALAUDIN © task 1) The CS 2 lasted for one minute, consisted of calibrated WN at 75dB SPL and was accompanied by 19 instances of calibrated 1000Hz tones at 74dB SPL. The intervals between tones ranged from 0.9 seconds to 5.4 seconds. 3) CS 3 (WN + ALAUDIN © task 2) A one-minute duration of white noise (WN), calibrated at 75dB SPL, was accompanied by 11 two-syllable words, including six animal names and five transport names. These words were calibrated to have an average sound pressure level (SPL) of 74dB. The interval between consecutive words was 5.4 seconds. 4) CS 4 (WN + ALAUDIN © task 3) A one-minute duration of white noise (WN) calibrated at 75dB SPL incorporated four instances of a 1000Hz tone, each calibrated to 74dB SPL and lasting 0.1 seconds. Subsequently, seven words (comprising four letters and three numbers) were presented randomly and calibrated to an average of 74dB SPL. The fixed interval between signals was set at 5.4 seconds. Procedure Participants underwent comprehensive clinical assessments, including an otoscopic examination, tympanometry, acoustic stapedial reflex (ASR) test, pure tone audiometry (PTA), and routine transient otoacoustic emission (TEOAE) testing. The otoscopic examination ensured the ear canal was clear and the tympanic membrane was intact. Tympanometry and ASR tests, conducted with the IMP440 DIAGNOS, aimed to rule out middle ear pathologies. A type A tympanogram and passed ASR screenings at frequencies of 500Hz, 1000Hz, and 2000Hz indicated the absence of such issues. Hearing screening was performed using the AC 40 clinical audiometer with a 25dB cut-off point across tested frequencies (250Hz, 500Hz, 1000Hz, 2000Hz, 3000Hz, 4000Hz, 6000Hz, and 8000Hz). All subjects exhibited robust transient otoacoustic emissions (TEOAEs), recorded at 80dB SPL click sound with a non-linear setting using the ILOv6 TEOAE analyser connected to an OTODYNAMICS Echoport. These covered frequencies of 1000, 1414, 2000, 2828, and 4000Hz. To obtain suppression, a 60dB SPL click sound with a linear setting was introduced to the tested ear. First, TEOAE amplitude without CS was measured. Then, a CS was delivered to the non-tested ear while re-measuring the TEOAE amplitude in the tested ear. For example, to get the TEOAE suppression for CS 1, TEOAE was initially recorded at 60dB using a click sound without the suppressor. Then, TEOAE was remeasured at the same stimulus intensity with the presence of CS 1 in the contralateral ear. Suppression values were determined by the difference between TEOAE amplitudes recorded without and with the CS presentation to the opposite ear. 26 The same procedure was applied for other CS, with the presentation randomized. For tasks requiring attention, subjects were required to stay alert and count the number of tones, animals, transports, letters, and numbers delivered to them. The entire procedure lasted approximately two hours. Statistical analysis All input data were analysed using Social Packages for the Social Sciences (SPSS) version 23.0 for Windows. The collected data from all subjects were meticulously entered, with subject confidentiality maintained through coding. Comprehensive analyses were conducted collectively. Descriptive analyses were performed to determine the frequency and percentage of the data. Independent sample t-tests were used to compare suppression between ears across all stimuli and groups. Additionally, one-way ANOVA was conducted to evaluate differences in the suppression of Transient Otoacoustic Emissions (TEOAEs) when different CS were used for each group. Declarations COMPETING INTEREST The authors declare no competing interests. Author Contribution All authors (C.M.A.C.A, N.M, S.A.M.T, M.N.Z, S.W and N.A.A.W) contributed equally to the production of this work. C.M.A.C.A, N.M, S.A.M.T, S.W and N.A.A.W involved in conceptualization, designation and investigation of the research. C.M.A.C.A, N.M, M.N.Z, S.W and N.A.A.W analyzed and wrote the paper. Acknowledgement The authors would like to thank the UKM ethics committee for approving this research study (JEP-2022-068) and the Centre for Innovation & Technology Transfer (INOVASI@UKM) for copyright approval to ALAUDIN© tasks (UKM.IKB.800-4/1/4034). The authors acknowledge the Fundamental Research Grant Scheme (FRGS), grant number (FRGS/1/2021/SKK06/UKM/02/4) funded by the Ministry of Higher Education (MOHE) Malaysia. This study would like to express profound gratitude to Mr Abdul Razak bin Rosli and Mrs Rosenadiah binti Muhin from Jabatan Pengurusan Kejururawatan, Hospital Canselor Tuanku Muhriz, UKM for their contributions to this study. Data Availability Our datasets do not fit into any of the categories specified in the guidelines for data deposition. No tissues or blood samples were collected from the subjects that warranted data analysis related to the datasets categories. Thus, we are unable to provide relevant accession numbers or links to databases. Secondly, the datasets analyzed in this study are not publicly available due to copyright issues associated with the tasks undertaken in this research, which were used to obtain the data. Additionally, the copyright involves two universities. To make this data publicly accessible, the appropriate legal procedures must be followed. Furthermore, due to the ethical guidelines of these universities, disclosure of research data to the public requires a multi-step legal procedure. The consent obtained from the vulnerable subjects includes a provision that their data will not be shared with non-research team members. 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Auditory Attention Reduced Ear-Canal Noise in Humans by Reducing Subject Motion, Not by Medial Olivocochlear Efferent Inhibition: Implications for Measuring Otoacoustic Emissions During a Behavioral Task. Frontiers in Systems Neuroscience 12 (2018). https://doi.org/10.3389/fnsys.2018.00042 Tahir, S. A. M. et al. Exploring the Effects of Alternate Auditory Attention Tasks on Electromotility of Cochlear Outer Hair Cells in Healthy Normal Hearing Adults. Auditory and Vestibular Research 33 , 142-151 (2024). https://doi.org/10.18502/avr.v33i2.14817 Akbari, M., Panahi, R., Valadbeigi, A. & Hamadi Nahrani, M. Speech-in-noise perception ability can be related to auditory efferent pathway function: a comparative study in reading impaired and normal reading children. Braz J Otorhinolaryngol 86 , 209-216 (2020). https://doi.org/10.1016/j.bjorl.2018.11.010 Källstrand, J., Nehlstedt, S. F., Sköld, M. L. & Nielzén, S. Lateral asymmetry and reduced forward masking effect in early brainstem auditory evoked responses in schizophrenia. Psychiatry Res 196 , 188-193 (2012). https://doi.org/10.1016/j.psychres.2011.08.024 Maruthy, S., Kumar, U. A. & Gnanateja, G. N. Functional Interplay Between the Putative Measures of Rostral and Caudal Efferent Regulation of Speech Perception in Noise. J Assoc Res Otolaryngol 18 , 635-648 (2017). https://doi.org/10.1007/s10162-017-0623-y Perrot, X. et al. Evidence for corticofugal modulation of peripheral auditory activity in humans. Cereb Cortex 16 , 941-948 (2006). https://doi.org/10.1093/cercor/bhj035 Maison, S., Micheyl, C. & Collet, L. Influence of focused auditory attention on cochlear activity in humans. Psychophysiology 38 , 35-40 (2001). https://doi.org/10.1111/1469-8986.3810035 Stephan, K. E., Friston, K. J. & Frith, C. D. Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring. Schizophr Bull 35 , 509-527 (2009). https://doi.org/10.1093/schbul/sbn176 Doucet, G. E., Luber, M. J., Balchandani, P., Sommer, I. E. & Frangou, S. Abnormal auditory tonotopy in patients with schizophrenia. npj Schizophrenia 5 , 16 (2019). https://doi.org/10.1038/s41537-019-0084-x Stripeikyte, G. et al. Fronto-Temporal Disconnection Within the Presence Hallucination Network in Psychotic Patients With Passivity Experiences. Schizophr Bull 47 , 1718-1728 (2021). https://doi.org/10.1093/schbul/sbab031 Ugur, A. K. et al. Otoacoustic emissions and effects of contralateral white noise stimulation on transient evoked otoacoustic emissions in diabetic children. Int J Pediatr Otorhinolaryngol 73 , 555-559 (2009). https://doi.org/10.1016/j.ijporl.2008.12.002 Prasher, D., Ryan, S. & Luxon, L. Contralateral suppression of transiently evoked otoacoustic emissions and neuro-otology. Br J Audiol 28 , 247-254 (1994). https://doi.org/10.3109/03005369409086574 Wahab, N. A. A., Wahab, S., Rahman, A. H. A., Sidek, D. & Zakaria, M. N. The hyperactivity of efferent auditory system in patients with schizophrenia: A transient evoked otoacoustic emissions study. Psychiatry Investigation 13 , 82-88 (2016). https://doi.org/10.4306/pi.2016.13.1.82 Veuillet, E. et al. Abnormal peripheral auditory asymmetry in schizophrenia. J Neurol Neurosurg Psychiatry 70 , 88-94 (2001). https://doi.org/10.1136/jnnp.70.1.88 Stuart, A. & Cobb, K. M. Reliability of measures of transient evoked otoacoustic emissions with contralateral suppression. J Commun Disord 58 , 35-42 (2015). https://doi.org/10.1016/j.jcomdis.2015.09.003 Steinmann, S., Leicht, G. & Mulert, C. The interhemispheric miscommunication theory of auditory verbal hallucinations in schizophrenia. Int J Psychophysiol 145 , 83-90 (2019). https://doi.org/10.1016/j.ijpsycho.2019.02.002 Ershaid, H. et al. Contributions of listening effort and intelligibility to cortical tracking of speech in adverse listening conditions. Cortex 172 , 54-71 (2024). https://doi.org/https://doi.org/10.1016/j.cortex.2023.11.018 Peelle, J. E. Listening Effort: How the Cognitive Consequences of Acoustic Challenge Are Reflected in Brain and Behavior. Ear Hear 39 , 204-214 (2018). https://doi.org/10.1097/aud.0000000000000494 McCutcheon, R. A., Keefe, R. S. E. & McGuire, P. K. Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment. Molecular Psychiatry 28 , 1902-1918 (2023). https://doi.org/10.1038/s41380-023-01949-9 Collinson, S. L., Mackay, C. E., O, J., James, A. C. & Crow, T. J. Dichotic listening impairments in early onset schizophrenia are associated with reduced left temporal lobe volume. Schizophr Res 112 , 24-31 (2009). https://doi.org/10.1016/j.schres.2009.03.034 Ford, J. M. & Mathalon, D. H. Efference Copy, Corollary Discharge, Predictive Coding, and Psychosis. Biol Psychiatry Cogn Neurosci Neuroimaging 4 , 764-767 (2019). https://doi.org/10.1016/j.bpsc.2019.07.005 Ceraso, A. et al. Maintenance treatment with antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev 8 , Cd008016 (2020). https://doi.org/10.1002/14651858.CD008016.pub3 Gehmacher, Q. et al. Direct Cochlear Recordings in Humans Show a Theta Rhythmic Modulation of Auditory Nerve Activity by Selective Attention. J Neurosci 42 , 1343-1351 (2022). https://doi.org/10.1523/jneurosci.0665-21.2021 Gruzelier, J. H. Hemispheric imbalances in schizophrenia. Int J Psychophysiol 1 , 227-240 (1984). https://doi.org/10.1016/0167-8760(84)90043-6 Steinberg, J. L., Devous, M. S., Paulman, R. G. & Gregory, R. R. Regional cerebral blood flow in first break and chronic schizophrenic patients and normal controls. Schizophr Res 17 , 229-240 (1995). https://doi.org/10.1016/0920-9964(96)81012-7 Kasai, K. et al. Progressive decrease of left superior temporal gyrus gray matter volume in patients with first-episode schizophrenia. Am J Psychiatry 160 , 156-164 (2003). https://doi.org/10.1176/appi.ajp.160.1.156 Vita, A., De Peri, L., Deste, G. & Sacchetti, E. Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies. Translational Psychiatry 2 , e190-e190 (2012). https://doi.org/10.1038/tp.2012.116 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5163811","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":374408368,"identity":"bd383157-b18e-4b79-961a-00236a634981","order_by":0,"name":"Che Muhammad Amir Che Awang","email":"","orcid":"","institution":"Universiti Kebangsaan Malaysia","correspondingAuthor":false,"prefix":"","firstName":"Che","middleName":"Muhammad Amir Che","lastName":"Awang","suffix":""},{"id":374408369,"identity":"93c3173c-ba5e-4028-99bf-9c8617c6c0c1","order_by":1,"name":"Noor Alaudin Abdul Wahab","email":"","orcid":"","institution":"Universiti Kebangsaan Malaysia","correspondingAuthor":false,"prefix":"","firstName":"Noor","middleName":"Alaudin Abdul","lastName":"Wahab","suffix":""},{"id":374408370,"identity":"d4e38186-df70-4f88-8f6f-01a45025e05e","order_by":2,"name":"Nashrah Maamor","email":"","orcid":"","institution":"Universiti Kebangsaan Malaysia","correspondingAuthor":false,"prefix":"","firstName":"Nashrah","middleName":"","lastName":"Maamor","suffix":""},{"id":374408371,"identity":"2e16341b-ae09-4d18-a151-4e6d341ae725","order_by":3,"name":"Siti Aisyah Mohammad Tahir","email":"","orcid":"","institution":"Universiti Kebangsaan Malaysia","correspondingAuthor":false,"prefix":"","firstName":"Siti","middleName":"Aisyah Mohammad","lastName":"Tahir","suffix":""},{"id":374408373,"identity":"4958ef34-9e3b-4a02-822d-0ced9437bfce","order_by":4,"name":"Mohd. Normani Zakaria","email":"","orcid":"","institution":"Universiti Sains Malaysia","correspondingAuthor":false,"prefix":"","firstName":"Mohd.","middleName":"Normani","lastName":"Zakaria","suffix":""},{"id":374408375,"identity":"f9ca2496-3442-4655-8b3b-f3282afe5f36","order_by":5,"name":"Suzaily Wahab","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYLCChAIGOSDFDGIbgAgJwloMGIxJ1AJUl9hAtBb5GekPPzwwOJy+XbrH2OgGw2Fj3Qbmg7d5GLaBDMFu/o2EZIkEg8O5O+ecMU7OYThsZnaALdmah+E2bi0SCQfAWjbcyDE+DNRiY3aAx0wanxb5GYnNP4Ba0g0QWvi/4dXCcCOZDWRLAkgL1GE8bHi1GJx5xmaRYJBuuHPOsWLjHIN0Y7PDbMaWcwxuG+N0WHv645s/KqzlzaWbN0vnVFgbbjve/PDGm4rbsjgdBgHNwHAAW8oAjx5HAlrqoFqQgD1+HaNgFIyCUTCCAABiGVeXn5j4zAAAAABJRU5ErkJggg==","orcid":"","institution":"Universiti Kebangsaan Malaysia","correspondingAuthor":true,"prefix":"","firstName":"Suzaily","middleName":"","lastName":"Wahab","suffix":""}],"badges":[],"createdAt":"2024-09-27 09:08:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5163811/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5163811/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-94412-4","type":"published","date":"2025-03-20T15:58:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69427402,"identity":"289851eb-07df-4580-ad1e-85a4566aabe8","added_by":"auto","created_at":"2024-11-20 08:57:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":27089,"visible":true,"origin":"","legend":"\u003cp\u003eBar chart of mean suppression by group for each suppressor. CS1: Contralateral Suppressor 1, CS2: Contralateral Suppressor 2, CS3: Contralateral Suppressor 3, CS4: Contralateral Suppressor 4.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5163811/v1/728e3c53a375f5ac6c05ce45.png"},{"id":69428113,"identity":"ca5200fa-5bf2-4487-9078-8014cdb8444a","added_by":"auto","created_at":"2024-11-20 09:05:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35261,"visible":true,"origin":"","legend":"\u003cp\u003eBar chart of mean TEAOE suppression between contralateral suppressors for each group. CS1: Contralateral Suppressor 1, CS2: Contralateral Suppressor 2, CS3: Contralateral Suppressor 3, CS4: Contralateral Suppressor 4.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5163811/v1/acecfdfed4247716fe3f6b26.png"},{"id":79120530,"identity":"07c97a0d-84cb-44aa-ab7c-95cc590bdae7","added_by":"auto","created_at":"2025-03-24 16:09:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":744957,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5163811/v1/edd509d9-5292-40a2-94a9-fdc15219450f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eDetecting Verbal Auditory Hallucination Among Schizophrenia Patients by Integrating Alternate Auditory Attention Tasks in Contralateral Suppression of Otoacoustic Emissions\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSchizophrenia is a multidimensional neuropsychiatric disorder that affects approximately 1% of the global population. Schizophrenia poses significant economic and social challenges to individuals, families, and society as a whole. Verbal auditory hallucinations (VAHs) are among the most distressing symptoms associated with schizophrenia. It is estimated that 60 to 90 percent of people with schizophrenia suffer from VAHs. Despite the fact that the mechanisms underlying these hallucinations remain poorly understood, studies have begun to explore the neurobiological and cognitive aspects of the phenomenon. It has been suggested that disconnection of brain regions such as the temporal lobe and prefrontal cortex may play a role in auditory hallucinations.\u003csup\u003e1\u003c/sup\u003e Understanding VAH is crucial to developing treatment and rehabilitation strategies that address patients' needs and improve their social functioning. For instance, several studies examining neurofeedback training have suggested that individuals suffering from VAH may benefit from this training, since it may help them gain control of their experiences by self-regulating brain activity in related networks.\u003csup\u003e2\u003c/sup\u003e Hence, research on auditory modalities and audiological assessments can further advance our understanding of these phenomena in schizophrenia.\u003c/p\u003e \u003cp\u003eAuditory hallucinations are defined as sensory perceptions of hearing in the absence of an external stimulus. Subjective evaluation of auditory hallucinations is typically conducted through clinical interviews and self-report measures such as Auditory Hallucinations Risk Assessment Scale and The Psychotic Symptom Rating Scales.\u003csup\u003e3,4\u003c/sup\u003e It is important to note that the experience of auditory hallucinations is highly individual, and subjectiveevaluation helps clinicians and researchers understand the nature and impact of these hallucinations on an individual's life. While subjective evaluation methods provide valuable insights into the individual experience of auditory hallucinations, they have certain limitations that should be considered. These limitations include, but are not limited to subjectivity and reliability, limited observability, memory recall and response biases, and psychological and emotional biases.\u003csup\u003e5,6\u003c/sup\u003e In the context of an interview, patient reports are highly susceptible to manipulation, making them inconsistent with psychiatrist observations. To overcome these limitations, a thorough evaluation of auditory hallucinations may include both subjective assessments and objective measures like neuroimaging. Objective tests, such as functional Magnetic Resonance Imaging (fMRI), can be used to investigate brain abnormalities, including issues with neural networks and dysconnectivity.\u003csup\u003e7,8\u003c/sup\u003e Although fMRI is non-invasive, it is both very costly and time-consuming. Hence, the current study investigates the potential of integrating ALternate AUDItory AttentioN (ALAUDIN\u0026copy;) tasks with Contralateral Suppression of Otoacoustic Emissions (CSOAE) in detecting auditory hallucinations in schizophrenia patients.\u003c/p\u003e \u003cp\u003eOtoacoustic emissions (OAE) is a rapid, relatively cost-effective and objective test to non-invasively measure the micromechanics of cochlea outer hair cells. OAE was introduced by Kemp\u003csup\u003e9\u003c/sup\u003e where he explained how the motility of healthy outer hair cells (OHCs) of the cochlea produces low energy sound pressure which is measured in the outer ear canal. OAE magnitude of at least 6dB above the noise floor reflects healthy and intact outer hair cells. Interestingly, the motility of cochlea OHCs can be suppressed by two efferent auditory pathways, namely caudal and rostral which are located at the lower brainstem and higher auditory centre respectively. The efferent auditory pathway plays an important role in regulating the outer hair cells of the cochlea.\u003csup\u003e10\u003c/sup\u003e The current belief is the caudal section, which consists of medial olivocochlear bundle (MOCB), acts as a contralateral reflex pathway to suppress OHCs of a tested ear with the presence of white noise in the contralateral (non-tested) ear. The efferent MOC did not play a crucial role in changing the micromechanics of outer hair cells in response to auditory attention or behavioral tasks.\u003csup\u003e11,12\u003c/sup\u003e The conclusion is based on the finding that there are no significant changes in the level of noise in the external ear canal, the magnitude of OAE, and the strength of the MOC reflex when normal subjects are given a multi-modality attention task and a range of auditory focus difficulties. For now, white noise has been successfully used as a suppressor in studies related to CSOAE. On the other hand, the role of the rostral section of the efferent auditory pathway is still less understood. The lack of understanding could be due to the anatomical complexity of the pathway which consists of the cortico-olivocochlear bundle (COCB). The COCB communicates with the caudal efferent pathways at the lower brainstem which eventually affect the electromotility of the OHCs. We speculate that to suppress the OHC via the rostral efferent pathway, the contralateral suppressors should have the ability to at least stimulate the auditory cortex. Activation of the auditory cortex would stimulate the rostral which eventually suppresses the cochlea outer hair cells via the caudal pathway. This is consistent with a previous study where electrical stimulation of the auditory cortex can reduce the magnitude of OAE. In fact, our recent study of the effect of contralateral ALAUDIN\u0026copy; tasks suggests the positive effect on healthy normal-hearing adults.\u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCurrently, there are no non-invasive, cost-effective, and objective tests that can rapidly detect verbal auditory hallucinations (VAH) in schizophrenia patients. This study, therefore, explores the integration of ALAUDIN\u0026copy; tasks into contralateral suppression otoacoustic emission (CSOAE) testing. This integrated ALAUDIN\u0026copy;-CSOAE approach aims to distinguish schizophrenia patients with VAH from those without it. The development of this method is based on the following concepts:\u003c/p\u003e \u003cp\u003eIn humans, efferent (top-down) auditory pathways exist alongside afferent pathways.\u003csup\u003e14\u003c/sup\u003e This is anatomically supported by the presence of the medial olivocochlear bundle (MOCB) in the caudal section and the cortico olivocochlear bundle (COCB) in the rostral section of the central auditory system.\u003csup\u003e15\u003c/sup\u003e The caudal section transmits electrical signals from the superior olivary complex (SOC) to its ipsilateral counterpart and partially to its contralateral counterpart. The rostral section is more complex, consisting of nerve fibres that originate in the auditory cortex, synapse with both ipsilateral and contralateral SOC, and ultimately innervate the basal portion of outer hair cells (OHCs).\u003csup\u003e16\u003c/sup\u003e As a result, auditory-related activities in the auditory cortices can indirectly influence the micromechanics of cochlear OHCs. Activities such as auditory attention, which involve active communication between the pre-frontal lobes and auditory cortices, may also affect OHC micromechanics. Activating the auditory cortex engages the efferent pathway, altering the cochlea's micromechanics. Studies have shown that activation of the auditory cortex by electrical stimulation\u003csup\u003e17\u003c/sup\u003e and selective attention\u003csup\u003e10\u003c/sup\u003e can modify the micromechanics of the OHC. Processing auditory information is also associated with prefrontal cortex activity, especially when selective attention is engaged.\u003csup\u003e18\u003c/sup\u003e Some of the problems with this relationship may affect sound processing in the auditory cortex, which in turn may affect efferent pathways and the OHC. In schizophrenia patients, the disconnectivity among brain regions, i.e. pre-frontal lobe and auditory cortex, causes the auditory cortex to function abnormally\u003csup\u003e19,20\u003c/sup\u003e and leads to auditory hallucinations.\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBy measuring changes in OHC micromechanics, it is possible to assess the integrity of the auditory efferent pathways. To achieve this, otoacoustic emission (OAE) amplitudes must be recorded both in the absence and presence of contralateral stimulation.\u003csup\u003e22\u003c/sup\u003e In an intact auditory pathway, a contralateral stimulus reduces OAE amplitude. Contralateral suppression is generally defined as the positive difference in OAE amplitude with and without the presence of contralateral stimulation, such as noise. The normal range of contralateral suppression is reported to be between 1.0 to 3.0dB when white noise is used as a stimulus.\u003csup\u003e23\u003c/sup\u003e However, in the CSOAE routine, white noise is believed to activate only the caudal section, whereas auditory attention tasks are thought to activate the rostral section.\u003c/p\u003e \u003cp\u003eA previous study found that schizophrenia patients exhibit higher suppression values compared to normal individuals, suggesting hyperactivity in the efferent pathway, particularly due to the automatic functioning of the auditory cortex.\u003csup\u003e24\u003c/sup\u003e Another study reported no significant difference in CSOAE values between schizophrenia patients and normal individuals.\u003csup\u003e25\u003c/sup\u003e However, these studies did not account for the effect of VAH in their subject selection criteria. Therefore, the current study aims to determine the effects of VAH on the efferent pathways by applying the Integrated ALAUDIN\u0026copy;-CSOAE. In addition to white noise (WN), the ALAUDIN\u0026copy; tasks are designed to optimize the subjects\u0026rsquo; auditory attention, thereby activating the rostral section as much as possible. This involves using WN along with tone, WN along with speech, or WN along with both tone and speech. Given the potential dysconnectivity in cortical pathways, this study hypothesizes that there will be significant differences in CSOAE values between schizophrenia patients with and without VAH. If significant differences are found, this test could potentially be used in the future as an objective support tool for detecting hallucinations in a clinical setting.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eSociodemographic data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 outlines the demographic characteristics of the participants included in the study analysis. The normal healthy control group consisted of 57 individuals, with 35 males (61%) and 22 females (39%). In this group, 52 right ears (48%) and 57 left ears (52%) were considered for the study. The S\u003csub\u003eAC\u003c/sub\u003e group comprised 5 individuals, with 2 males (40%) and 3 females (60%). For this group, both left and right ears were equally represented, with 5 ears (50%) each. The S\u003csub\u003ePA\u003c/sub\u003e group included 5 male patients exclusively, with 4 left ears (44%) and 5 right ears (66%) analysed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e\u0026nbsp; Demographic data of subjects\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"601\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 113px;\"\u003e\n \u003cp\u003eSubjects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 145px;\"\u003e\n \u003cp\u003eEar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 142px;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 116px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003ePercentage\u003c/p\u003e\n \u003cp\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 56px;\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eHC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e85.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eS\u003csub\u003eAC\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e7.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eS\u003csub\u003ePA\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e7.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eHC = healthy control; S\u003csub\u003eAC\u003c/sub\u003e = schizophrenia with active hallucination; S\u003csub\u003ePA\u003c/sub\u003e = schizophrenia with passive hallucination.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTEOAE Suppression between ears across groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 presents a comparison of mean TEOAE suppression between ears across different groups. In the HC group, there was no statistically significant difference in TEOAE suppression between the left and right ears for all CS (p\u0026gt;0.05). However, the mean TEOAE suppression in the left ear tended to be higher compared to the right ear for each CS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. Comparison of mean suppression between ears across groups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 98px;\"\u003e\n \u003cp\u003eContralateral Suppressors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 168px;\"\u003e\n \u003cp\u003eHC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 168px;\"\u003e\n \u003cp\u003eS\u003csub\u003eAC\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 168px;\"\u003e\n \u003cp\u003eS\u003csub\u003ePA\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eRE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eLE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003ep* value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eRE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eLE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003ep* value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eRE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003eLE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003ep* value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003eCS1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e1.408\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e1.632\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.377\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e3.200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e-0.820\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e3.200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e2.725\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e2.620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e0.982\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003eCS2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e1.394\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e1.596\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.516\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e2.620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e2.440\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e2.620\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e2.350\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e0.840\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e0.705\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003eCS3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e1.400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e1.623\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.821\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e1.660\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e1.960\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e1.660\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e-0.500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e3.220\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e0.328\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003eCS4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e1.156\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e1.332\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e0.559\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e2.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e4.820\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e2.040\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e3.625\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e2.140\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e0.665\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eHC: healthy control, S\u003csub\u003eAC\u003c/sub\u003e: Schizophrenia with active hallucination, S\u003csub\u003ePA\u003c/sub\u003e: schizophrenia with passive hallucination; CS1: Stimulus 1; CS2: Stimulus 2; CS3: Stimulus 3; CS4: Stimulus 4.\u003c/p\u003e\n\u003cp\u003eSimilarly, in the S\u003csub\u003eAC\u003c/sub\u003e group, there was no statistically significant difference in TEOAE suppression between the left and right ears for all CS (p\u0026gt;0.05). However, the mean suppression patterns varied inconsistently between ears with different CS.\u003c/p\u003e\n\u003cp\u003eIn the S\u003csub\u003ePA\u003c/sub\u003e group, there was no statistically significant difference in TEOAE suppression between the left and right ear for all CS (p \u0026gt; 0.05). However, the mean suppression was mostly higher in the right ear than in the left ear, except in CS 3.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTEOAE suppression by group for each suppressor\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 represents the mean of TEOAE suppression measured across groups for each CS. Combining data from both ears for each group, since there were no significant differences between them, revealed no statistically significant difference in suppression between the groups when using CS1, CS2 and CS3 (p\u0026gt;0.05). However, when using CS4, the difference became statistically significant, with an F value of (2.125) = 5.853 and p=0.004. Moreover, suppression was found to be larger in the S\u003csub\u003eAC\u003c/sub\u003e group (M=3.4, SD=4.67) compared to the HC group (M=1.2, SD=1.56), showing a mean difference of 2.18 with a 95% confidence interval of [0.42, 3.95], which was statistically significant (p=0.011).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTEOAE suppression by suppressors for each group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 2 shows the mean TEOAE suppression measured across suppressors for each group. Across all groups, using different CS did not result in any statistically significant changes in TEOAE suppression (p\u0026gt;0.05). However, in the S\u003csub\u003eAC\u003c/sub\u003e group, using suppressors CS2, CS3, and CS4 (which contain ALAUDIN\u003csup\u003e\u0026copy;\u003c/sup\u003e tasks) descriptively showed larger suppression compared to suppressor S1, which does not include a task (Figure 2).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003e In this study, we explored a novel approach which is integrating ALAUDIN\u0026copy; tasks with Contralateral Suppression of Otoacoustic Emissions (CSOAE), to detect verbal auditory hallucinations (VAH) in schizophrenia patients. This research is based on two main premises. First, it addresses the limitations of routine subjective (i.e. questionnaires) and objective methods (i.e. fMRI) in identifying VAH. However, it is important to emphasize that the Integrated ALAUDIN\u0026copy;-CSOAE approach is intended to complement rather than replace these existing methods, offering advantages in terms of time, objectivity, non-invasiveness, and cost-effectiveness. Second, the study is motivated by theories of brain dysconnectivity\u003csup\u003e21\u003c/sup\u003e and interhemispheric miscommunication\u003csup\u003e26\u003c/sup\u003e in explaining VAH, which are attributed to the automatic activation of the auditory cortex. These theories led us to investigate how complex auditory attention tasks might impact the rostral and caudal efferent auditory pathways and, consequently, the micromechanics of cochlear outer hair cells (OHC). The communication between prefrontal areas and auditory cortices plays a crucial role in attention to auditory stimuli, suggesting that challenging auditory attention tasks could have significant implications and open new avenues for future research.\u003c/p\u003e \u003cp\u003eAs suppression values between ears across all groups showed no significant difference, we combined the values between ears for each group. The results revealed significant differences of TEOAE suppression between groups by using CS4, but not for another CS. Furthermore, post hoc test revealed significant differences in suppression between S\u003csub\u003eAC\u003c/sub\u003e and HC groups. Interestingly, there was no significant difference in suppression between schizophrenia patients with passive hallucinations (S\u003csub\u003ePA\u003c/sub\u003e) with either S\u003csub\u003eAC\u003c/sub\u003e or HC. These findings suggest three significant implications. First, by integrating ALAUDIN\u0026copy; task into CSOAE, which engage auditory attention, we can provide added value to routine CSOAE in assessing the intactness of the efferent auditory pathway, specifically among patients with schizophrenia. Secondly, our findings support previous literatures on automated activation of the auditory cortex during active hallucinations. This causes hyperactivity of the efferent auditory pathways that, in turn, leads to large suppression of OAE. Third, when engaging in an auditory task that requires understanding speech over a long duration, the primary factor in successfully completing such tasks is listening effort which is derived from cognitive ability.\u003csup\u003e27,28\u003c/sup\u003e However, individuals with schizophrenia often experience deficits in cognitive functions, including temporal processing, which is essential for understanding speech.\u003csup\u003e29\u003c/sup\u003e Hence, the study argues that effort required for individuals with schizophrenia to perform auditory tasks is significantly higher than that of people without the condition. This increased effort likely results in heightened activity in the auditory cortex, which may be more pronounced in schizophrenia patients compared to the control group. Although the precise nature of the relationship between listening effort and auditory cortex activation in schizophrenia patients is not yet fully understood, this connection warrants further investigation. Understanding this relationship could provide insights into the neural mechanisms underlying auditory processing deficits in schizophrenia and help inform more effective therapeutic approaches.\u003c/p\u003e \u003cp\u003eThe significantly larger suppression with CS4 in S\u003csub\u003eAC\u003c/sub\u003e compared to HC aligns with previous research, supporting the hyperactivity theory, which suggests that individuals with schizophrenia especially experience VAH exhibit higher levels of OAE suppression compared to normal subjects due to increased activity in the auditory cortex.\u003csup\u003e24\u003c/sup\u003e Moreover, the observation of descriptively larger suppression in S\u003csub\u003eAC\u003c/sub\u003e compared to S\u003csub\u003ePA\u003c/sub\u003e lend further credence to the notion that auditory hallucinations may influence the micro-mechanics of outer hair cells, possibly due to dysconnectivity in the brain\u003csup\u003e15,30\u003c/sup\u003e which finally generate auto activation of auditory cortex. This dysconnectivity, particularly affecting the temporo-prefrontal neuronal circuit, may involve deficits in corollary discharge, which normally suppresses activities in the auditory cortex, thereby reducing stimulation of the efferent pathway.\u003csup\u003e31\u003c/sup\u003e Furthermore, alterations in GABA production disrupt the delicate balance of neurotransmitters in the auditory system, leading to an increase in acetylcholine release. This excess acetylcholine triggers hypersensitivity in the outer hair cells, culminating in hyperpolarization and reduced responsiveness to auditory stimuli, ultimately contributing to diminished OAE amplitudes. These findings offer new insights into the potential use of OAE suppression with auditory attention tasks for differentiating between schizophrenia patients with and without hallucinations and normal individuals. Hence, we hypothesize that introducing auditory attention tasks, particularly those that are more challenging, to individuals with disrupted brain area communication will enhance or trigger increased neural firing in the associated brain regions. This increased neural activity may ultimately result in hyperactivity of the efferent pathways.\u003c/p\u003e \u003cp\u003eThe observations of suppression in S\u003csub\u003ePA\u003c/sub\u003e could be explained by considering the group as an overlapping population between HC and S\u003csub\u003eAC\u003c/sub\u003e. In other words, the condition experienced by S\u003csub\u003ePA\u003c/sub\u003e may represent a transitional phase between HC and S\u003csub\u003eAC\u003c/sub\u003e. The overlap could indicate that S\u003csub\u003ePA\u003c/sub\u003e is shifting to either normal or abnormal efferent auditory processing which is influenced by neurochemical stability (i.e. not experiencing VAH) or imbalances (experiencing VAH), in particular the dopamine and glutamate systems, in S\u003csub\u003ePA\u003c/sub\u003e. As a result, neural activity and communication may be affected, possibly contributing to the overlap observed between S\u003csub\u003ePA\u003c/sub\u003e and HC or S\u003csub\u003eAC\u003c/sub\u003e. Additionally, dysconnectivity between cortical regions, at least in the auditory-attention area, and cortical-subcortical functional connectivity have likely improved. Furthermore, improved GABAergic levels may also affect the efferent auditory pathway, leading to a more functional auditory pathway close to normal. Persistent intake and maintenance of atypical antipsychotic are believed may reduce the acute symptoms especially VAH.\u003csup\u003e32\u003c/sup\u003e Hence, it is crucial to consider the classification of patients into S\u003csub\u003eAC\u003c/sub\u003e and S\u003csub\u003ePA\u003c/sub\u003e categories. Even though S\u003csub\u003ePA\u003c/sub\u003e patients are categorized as not experiencing hallucinations, abnormalities may still be present in these individuals. Additionally, the classification of passive hallucination may overlook instances where subtle hallucinations may occur intermittently, potentially leading to non-significant findings.\u003c/p\u003e \u003cp\u003eOur findings indicate a greater suppression in the left ear compared to the right ear in the HC group across all CS, aligning with observations from other studies.\u003csup\u003e24\u003c/sup\u003e However, this difference between ears is not statistically significant. This may be attributed to the compromised function between the left and right hemispheres in healthy individuals, which supports their role in auditory processing.\u003csup\u003e33\u003c/sup\u003e This is further supported by the normal function of NMDAR (N-methyl-D-aspartate receptor) in HC, which facilitates intact inter-hemispheric and inter-regional brain communication, particularly between prefrontal and auditory brain areas.\u003csup\u003e26\u003c/sup\u003e Such functionality ensures balanced neurochemical processes and intact excitatory/inhibitory efferent function. Additionally, Gehmacher, et al. \u003csup\u003e34\u003c/sup\u003e propose that an unknown, yet crucial, mutual compensation mechanism between cortical and OHC modulation results in an insignificant difference in MOC reflexes measured with various contralateral auditory suppressors. Collectively, these factors suggest the lack of a significant difference in TEOAE suppression between ears in HC subjects.\u003c/p\u003e \u003cp\u003eIn both the S\u003csub\u003eAC\u003c/sub\u003e and S\u003csub\u003ePA\u003c/sub\u003e groups, our study also did not find a significant difference in suppression between ears, suggesting a lack of asymmetry, similar to the findings of Veuillet and colleagues\u003csup\u003e25\u003c/sup\u003e, who used an equivalent equation technique to determine MOC function. Although the suggestion aligns, discussing the differences in approaches between the studies remains valuable. Unlike Veuillet et al.\u003csup\u003e25\u003c/sup\u003e, the current study employed auditory attention tasks for the subjects. We propose that, beyond the absence of a right ear advantage (REA) in schizophrenia patients, the observed lack of asymmetry may also be linked to the disrupted function of NMDAR receptors in these patients. NMDAR dysfunction results in miscommunication between hemispheres, which is compensated by an increased release of glutamate from the frontal and auditory cortex. This compensation may account for the overall differences observed between schizophrenia patients and healthy controls, but not for the inter-ear differences within the schizophrenia group.\u003c/p\u003e \u003cp\u003eHowever, other studies argued that individuals with schizophrenia tend to exhibit asymmetry of suppression between ears. Hemispheric imbalances were reported in individuals with schizophrenia, particularly those experiencing auditory hallucinations.\u003csup\u003e35\u003c/sup\u003e This imbalance may be attributed to a greater regional cerebral blood flow (rCBF) in the right temporal lobe compared to the left, resulting in heightened neuronal activity in the right temporal lobe.\u003csup\u003e36\u003c/sup\u003e This increased activity may specifically affect the efferent auditory pathway, leading to greater suppression observed in the left outer hair cells (OHCs). However, it's essential to note that these findings do not necessarily imply functional decline in the left temporal lobe. Instead, they raise intriguing questions about the reasons behind the heightened blood flow and activity in the right temporal lobe, potentially leading to overactivity in this region. Furthermore, reports of decreased volume mass in the left temporal lobe,\u003csup\u003e37,38\u003c/sup\u003e add complexity to our understanding, suggesting that lesions may manifest differently among schizophrenia patients. Although there are some discrepancies between the current study and previous research, such as the classification of schizophrenia patients based on active and passive hallucinations, and the small sample size, these variations may have influenced the statistical analyses. A larger sample size in each group could potentially yield more significant differences between the ears, enhancing our understanding of auditory processing abnormalities in schizophrenia.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn summary, the integration of ALAUDIN\u0026copy;-CSOAE is potential in distinguishing individuals with schizophrenia experiencing active auditory hallucinations as they exhibit larger suppression compared to others. This observation is likely due to dysconnectivity leading to hyperactivity in the efferent auditory pathway. Additionally, the more challenging attention tasks, as evidenced by CS4, appears to impact schizophrenia with hallucinations more by significantly increasing suppression values compared to HC group. Lastly, to bolster confidence in this diagnostic tool, further studies with larger sample sizes are necessary. Additionally, assessing the accuracy of this test is vital and could pave the way for an objective, rapid, non-invasive, and cost-effective diagnostic tool for identifying patients with auditory hallucinations.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003eThe study involved 57 healthy controls (HC) and 10 individuals diagnosed with schizophrenia, aged between 18 and 40 years. Among the schizophrenia patients, five were experiencing active auditory hallucinations (S\u003csub\u003eAC\u003c/sub\u003e), while another five were experiencing passive auditory hallucinations (S\u003csub\u003ePA\u003c/sub\u003e). Auditory hallucinations that occurred within the previous two weeks, including the day of evaluation, were considered active auditory hallucinations (AH). Passive auditory hallucinations are those in which the participant has not experienced auditory hallucinations for at least two weeks, including the day of the evaluation. All schizophrenia patients were being treated with atypical antipsychotic medications. Importantly, none of the participants, whether healthy or diagnosed with schizophrenia, reported difficulty understanding conversations in either quiet or noisy environments. Additionally, none of them reported having ear disorders, tinnitus, or prolonged exposure to loud noises. The study received ethical approval from the Human Ethics Committee of UKM (JEP-2022-068). This study was performed following the guidelines by Human Ethics Committee of UKM and informed consent was obtained from all subjects.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eContralateral suppressors of TEAOEs\u003c/h2\u003e \u003cp\u003e \u003cb\u003eInstrumentation and stimulus\u003c/b\u003e. Audacity version 3.2.1, a multi-track audio editor and recorder for computers, was used for recording, editing, and generating contralateral suppressors (CS). A Sound Pro 1/3 Octave S/N BFL120002 sound level meter equipped with a 2cc coupler was used to calibrate each of the four CS listed below. In addition, these CS displayed high test-retest reliability.\u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e1) CS 1 (White noise only)\u003c/p\u003e \u003cp\u003eWhite noise (WN) calibrated at 75dB SPL for one minute.\u003c/p\u003e \u003cp\u003e2) CS 2 (WN\u0026thinsp;+\u0026thinsp;ALAUDIN\u003csup\u003e\u0026copy;\u003c/sup\u003e task 1)\u003c/p\u003e \u003cp\u003eThe CS 2 lasted for one minute, consisted of calibrated WN at 75dB SPL and was accompanied by 19 instances of calibrated 1000Hz tones at 74dB SPL. The intervals between tones ranged from 0.9 seconds to 5.4 seconds.\u003c/p\u003e \u003cp\u003e3) CS 3 (WN\u0026thinsp;+\u0026thinsp;ALAUDIN\u003csup\u003e\u0026copy;\u003c/sup\u003e task 2)\u003c/p\u003e \u003cp\u003eA one-minute duration of white noise (WN), calibrated at 75dB SPL, was accompanied by 11 two-syllable words, including six animal names and five transport names. These words were calibrated to have an average sound pressure level (SPL) of 74dB. The interval between consecutive words was 5.4 seconds.\u003c/p\u003e \u003cp\u003e4) CS 4 (WN\u0026thinsp;+\u0026thinsp;ALAUDIN\u003csup\u003e\u0026copy;\u003c/sup\u003e task 3)\u003c/p\u003e \u003cp\u003eA one-minute duration of white noise (WN) calibrated at 75dB SPL incorporated four instances of a 1000Hz tone, each calibrated to 74dB SPL and lasting 0.1 seconds. Subsequently, seven words (comprising four letters and three numbers) were presented randomly and calibrated to an average of 74dB SPL. The fixed interval between signals was set at 5.4 seconds.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eProcedure\u003c/h2\u003e \u003cp\u003eParticipants underwent comprehensive clinical assessments, including an otoscopic examination, tympanometry, acoustic stapedial reflex (ASR) test, pure tone audiometry (PTA), and routine transient otoacoustic emission (TEOAE) testing. The otoscopic examination ensured the ear canal was clear and the tympanic membrane was intact. Tympanometry and ASR tests, conducted with the IMP440 DIAGNOS, aimed to rule out middle ear pathologies. A type A tympanogram and passed ASR screenings at frequencies of 500Hz, 1000Hz, and 2000Hz indicated the absence of such issues.\u003c/p\u003e \u003cp\u003eHearing screening was performed using the AC 40 clinical audiometer with a 25dB cut-off point across tested frequencies (250Hz, 500Hz, 1000Hz, 2000Hz, 3000Hz, 4000Hz, 6000Hz, and 8000Hz). All subjects exhibited robust transient otoacoustic emissions (TEOAEs), recorded at 80dB SPL click sound with a non-linear setting using the ILOv6 TEOAE analyser connected to an OTODYNAMICS Echoport. These covered frequencies of 1000, 1414, 2000, 2828, and 4000Hz.\u003c/p\u003e \u003cp\u003eTo obtain suppression, a 60dB SPL click sound with a linear setting was introduced to the tested ear. First, TEOAE amplitude without CS was measured. Then, a CS was delivered to the non-tested ear while re-measuring the TEOAE amplitude in the tested ear. For example, to get the TEOAE suppression for CS 1, TEOAE was initially recorded at 60dB using a click sound without the suppressor. Then, TEOAE was remeasured at the same stimulus intensity with the presence of CS 1 in the contralateral ear. Suppression values were determined by the difference between TEOAE amplitudes recorded without and with the CS presentation to the opposite ear.\u003csup\u003e26\u003c/sup\u003e The same procedure was applied for other CS, with the presentation randomized. For tasks requiring attention, subjects were required to stay alert and count the number of tones, animals, transports, letters, and numbers delivered to them. The entire procedure lasted approximately two hours.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll input data were analysed using Social Packages for the Social Sciences (SPSS) version 23.0 for Windows. The collected data from all subjects were meticulously entered, with subject confidentiality maintained through coding. Comprehensive analyses were conducted collectively. Descriptive analyses were performed to determine the frequency and percentage of the data. Independent sample t-tests were used to compare suppression between ears across all stimuli and groups. Additionally, one-way ANOVA was conducted to evaluate differences in the suppression of Transient Otoacoustic Emissions (TEOAEs) when different CS were used for each group.\u003c/p\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCOMPETING INTEREST\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors (C.M.A.C.A, N.M, S.A.M.T, M.N.Z, S.W and N.A.A.W) contributed equally to the production of this work. C.M.A.C.A, N.M, S.A.M.T, S.W and N.A.A.W involved in conceptualization, designation and investigation of the research. C.M.A.C.A, N.M, M.N.Z, S.W and N.A.A.W analyzed and wrote the paper.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank the UKM ethics committee for approving this research study (JEP-2022-068) and the Centre for Innovation \u0026amp; Technology Transfer (INOVASI@UKM) for copyright approval to ALAUDIN\u0026copy; tasks (UKM.IKB.800-4/1/4034). The authors acknowledge the Fundamental Research Grant Scheme (FRGS), grant number (FRGS/1/2021/SKK06/UKM/02/4) funded by the Ministry of Higher Education (MOHE) Malaysia. This study would like to express profound gratitude to Mr Abdul Razak bin Rosli and Mrs Rosenadiah binti Muhin from Jabatan Pengurusan Kejururawatan, Hospital Canselor Tuanku Muhriz, UKM for their contributions to this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eOur datasets do not fit into any of the categories specified in the guidelines for data deposition. No tissues or blood samples were collected from the subjects that warranted data analysis related to the datasets categories. Thus, we are unable to provide relevant accession numbers or links to databases. Secondly, the datasets analyzed in this study are not publicly available due to copyright issues associated with the tasks undertaken in this research, which were used to obtain the data. Additionally, the copyright involves two universities. To make this data publicly accessible, the appropriate legal procedures must be followed. Furthermore, due to the ethical guidelines of these universities, disclosure of research data to the public requires a multi-step legal procedure. The consent obtained from the vulnerable subjects includes a provision that their data will not be shared with non-research team members. However, study may consider sharing the data upon reasonable request through the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBarber, L., Reniers, R. \u0026amp; Upthegrove, R. A review of functional and structural neuroimaging studies to investigate the inner speech model of auditory verbal hallucinations in schizophrenia. \u003cem\u003eTranslational Psychiatry\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 582 (2021). https://doi.org/10.1038/s41398-021-01670-7\u003c/li\u003e\n\u003cli\u003eHirano, Y. \u0026amp; Tamura, S. Recent findings on neurofeedback training for auditory hallucinations in schizophrenia. \u003cem\u003eCurr Opin Psychiatry\u003c/em\u003e \u003cstrong\u003e34\u003c/strong\u003e, 245-252 (2021). https://doi.org/10.1097/yco.0000000000000693\u003c/li\u003e\n\u003cli\u003eHaddock, G., McCarron, J., Tarrier, N. \u0026amp; Faragher, E. B. 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Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies. \u003cem\u003eTranslational Psychiatry\u003c/em\u003e \u003cstrong\u003e2\u003c/strong\u003e, e190-e190 (2012). https://doi.org/10.1038/tp.2012.116\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Schizophrenia, Efferent pathways, Otoacoustic emissions, Suppression","lastPublishedDoi":"10.21203/rs.3.rs-5163811/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5163811/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e Subjective evaluations of verbal auditory hallucinations (VAH) in schizophrenia have limitations; thus, combining them with objective measures like neuroimaging may provide more accurate insights into brain activity during VAH episodes. However, neuroimaging is often costly and time-consuming, prompting the search for alternative methods. This study explores the integration of ALternate AUDItory AttentioN (ALAUDIN\u0026copy;) tasks with Contralateral Suppression of Otoacoustic Emissions (CSOAE) as a rapid and cost-effective approach to detect VAH in schizophrenia patients. A total of 57 healthy controls (HC) and 10 schizophrenia patients; five with active and five with passive VAH; participated. Various contralateral stimuli, including white noise (WN) alone and WN combined with auditory attention tasks, were used to evaluate CSOAE. While no significant differences in suppression were found between the left and right ears across all groups, patients with active VAH demonstrated significantly higher suppression than HC for specific stimuli (CS4). Notably, incorporating ALAUDIN\u0026copy; tasks did not significantly enhance suppression in HC or patients with passive VAH but descriptively increased suppression in those with active VAH. These results suggest that ALAUDIN\u0026copy;-CSOAE may effectively differentiate schizophrenia patients with VAH from healthy individuals, warranting further research with larger sample sizes to validate these findings.\u003c/p\u003e","manuscriptTitle":"Detecting Verbal Auditory Hallucination Among Schizophrenia Patients by Integrating Alternate Auditory Attention Tasks in Contralateral Suppression of Otoacoustic Emissions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-20 08:57:20","doi":"10.21203/rs.3.rs-5163811/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-17T10:01:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-13T02:29:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"57718435832392128766870163353022349386","date":"2024-11-25T14:36:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-18T20:02:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"76051478448315809211727900669602076437","date":"2024-11-04T11:16:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-04T07:25:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-04T07:24:09+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-10-30T19:13:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-29T05:16:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-09-27T08:55:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7c2cd8ce-9614-4a1f-962c-6d8c87851110","owner":[],"postedDate":"November 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":39950548,"name":"Biological sciences/Neuroscience/Auditory system/Cochlea"},{"id":39950549,"name":"Biological sciences/Neuroscience/Auditory system/Hair cell"},{"id":39950550,"name":"Biological sciences/Neuroscience/Auditory system/Inner ear"}],"tags":[],"updatedAt":"2025-03-24T16:03:09+00:00","versionOfRecord":{"articleIdentity":"rs-5163811","link":"https://doi.org/10.1038/s41598-025-94412-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-03-20 15:58:06","publishedOnDateReadable":"March 20th, 2025"},"versionCreatedAt":"2024-11-20 08:57:20","video":"","vorDoi":"10.1038/s41598-025-94412-4","vorDoiUrl":"https://doi.org/10.1038/s41598-025-94412-4","workflowStages":[]},"version":"v1","identity":"rs-5163811","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5163811","identity":"rs-5163811","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}