Hearing loss and chronic vestibular pathologies require brain adaptive mechanisms supported by a cross-modal cortical plasticity. They are often accompanied by cognitive deficits. Spatial memory is a cognitive process responsible for recording information about the spatial environment and spatial orientation. Visual-spatial working memory (VSWM) is a kind of short-term working memory that allows spatial information to be temporarily stored and manipulated. It can be conditioned by hearing loss and also well-compensated chronic vestibular deficit. Vestibular rehabilitation and hearing aid devices or training are able to improve the VSWM. We studied 119 subjects suffering from perinatal or congenital hearing loss, compared with 532 healthy subjects and 404 patients with well-compensated chronic vestibular deficit (CVF). VSWM was evaluated by the eCorsi test. The subjects suffering from chronic hearing loss and/or unilateral or bilateral vestibular deficit showed a VSWM less efficient than healthy people, but much better than those with CVF, suggesting a better multimodal adaptive strategy, probably favored by a cross-modal plasticity which also provides habitual use of lip reading. The sport activity cancels the difference with healthy subjects. It is therefore evident that patients with this type of deficit since childhood should be supported and advised on a sport activity or repeated vestibular stimulation. Spatial memory is a cognitive process responsible for recording information about the spatial environment and spatial orientation. It enables a person to remember different locations as well as spatial relations between objects and it allows one to remember where an object is in relation to another object.Spatial working memory (SWM) is a kind of short-term working memory (WM) that allows spatial information to be temporarily stored and manipulated. It has a limited capacity and is quite vulnerable to interference.It is well known that the dorsolateral prefrontal cortex takes part in SWM thanks to a network, extending across several cortical areas, including the posterior parietal cortex, frontal eye field, supplementary motor area, premotor cortex, anterior cingulate cortex, occipital cortex, and hippocampal formation.In addition to being closely intertwined attentional and oculomotor programming, in particular related to saccadic movements, it has also been shown that SWM involves higher order cognitive processes, such as executive functioning, at the earliest stages of information processing. Thus, depending on strategies elaborated and task demands, the same spatial information may be represented in SWM by different patterns of activation in the brain.This view is consistent with a model of memory arising from the interaction between higher-order cognitive top-down processes governed by the prefrontal cortex and stimulus-specific brain regions. Visual attention has a cross-modal influence on activity in this network. The visual spatial exploration component provides information for the visual spatial working memory (VSWM).Spatial working memory problems are frequently reported following brain damage within both left and right hemispheres but with the severity often being greater in individuals with right hemisphere lesions.The increase in performance with advancing age supports the notion that SWM capacity increases with maturation throughout childhood with an ameliorative effect of education. It declines across the life span even in the absence of disease-related cerebral pathology.Sex differences are often reported in spatial abilities. Until a few years ago, it was widely accepted that men outperformed women on almost all spatial tasks. However, some studies show conflicting results, which can be ascribed to the complexity of the variables involved in the visuo-spatial domain, and can be better explained by differences in spatial competences. Indeed, these differences could reflect the use of different strategies, rather than different competences, used by the two sexes.Hearing loss and chronic vestibular pathologies require adaptive cerebral mechanisms capable of modifying the usual networks, they can interfere between themselves and thus, they are often accompanied by cognitive deficits which become clearer with aging ,2,3.In both pathological conditions, the adaptation is supported by a cross-modal cortical plasticity. Cross-modal plasticity refers to the phenomenon when deprivation in one sensory modality  results in the recruitment of cortical resources of the deprived modality by intact sensory modalities  ,5,6.In particular, the adaptation to vestibular deficit is considered an important example of this kind of neuronal plasticity. Thanks to wide central connections, the vestibular system is not merely involved in reflexes, but it is also connected to cognitive processes. A growing body of literature suggests that it has a substantial impact on cognitive function. These cognitive interactions include memory, attention, mental imagery, body awareness, and social cognition. Emerging research suggests that the vestibular system can be considered a potential window for exploring brain function beyond that of maintenance of balance, and into areas of cognitive, affective and psychiatric symptomology .Cognitive deficits occur frequently among patients with vestibular abnormalities of any type . BehavioChildren with VL show similar cognitive difficulties to adults, in tasks involving dynamic cognitive processes  that in tasks requiring static cognitive processes such as visual attention task .In addition, the relationship between peripheral hearing loss and cognition are well-documented in previous comprehensive reviews ,17.Particularly in mice, even only a moderate hearing loss is characterized by progressively poorer performances in spatial working and recognition memories, with more p-tau and lipofuscin in the hippocampus ,19.It has been speculated that hearing loss was associated with an increased rate of dementia diagnosed before age 60 , and thaHearing loss in children leads to various deficiencies, such as an impaired language, poorly developed reading and writing skills, difficulties in mnemonic learning, deficit in mathematical reasoning, and an inability to comprehend space and time.Hearing loss which arises in infancy can be considered a substantial signal of weakness  especially with aging; this leads to a deterioration in memory, perception, attention and linguistics.This condition, especially in children, represents a social isolation risk and a reduced capability to participate in social activities such as sports.Regarding this, it is worth mentioning that in Geneva in 1992 UNESCO  redacted the paper for the children’s rights in sport, and in 11 points it underlines that sport is a fundamental right for children and a commitment to exercise helps them to release tension and grow up healthy and fit.In particular, the paper underlines that parents must encourage physical exercise due to the notorious psychophysics advantages which cannot be regained in a later age, so parents must not deny children those possibilities.Severe hearing and vestibular deficits are often associated with patients with newborn and infant hearing loss. The balance training proved effective in improving SWM in healthy people ,23,24. VHearing devices (cochlear implants and bone-anchored hearing implant) can improve WM in children with sensorineural hearing loss ,28.In particular, children with cochlear implants demonstrated better performance in VSWM and short-term memory skills than in auditory working memory and auditory short-term memory skills. Significant positive relationships were found between visual working memory and reading outcomes .There is a lack of studies on the possibility that sport is able to interfere with any cognitive problems connected with the simultaneous hearing and vestibular deficit. We therefore considered the possibility of using VSWM to evaluate the ability of sports activity to improve cognitive functions.Collaborating with the scientific board of Ente Nazionale Sordi (ENS), specifically with the Milan and Reggio Emilia branches, and with the Federazione Sport Sordi Italia (FSSI) we examined 104 deaf individuals, divided into two groups; those over and those under 65 years old.The sample (ENS group) was composed of 77 men (74%) and 27 women (26%). The average age was 49 years old (SD 18). Participation was exclusively voluntary.Bilateral hearing loss was always present, severe in 26 individuals (25%) and profound in 78 (75%). The hearing loss was present at birth in 61 cases (58.6%), within the first year in 34 (32.8%), and within 13 years in the remaining 9 (8.6%).Hearing loss was hereditary in 41 cases (39.4%). The cause was unknown in 32 (30.8%), post-infective in 31 (29.8%).No individual had a cochlear implant.All the subjects examined communicate using correct sign language and lipreading.Only 32 subjects (30.8%) had had vertigo during their lifetime.Of the participants, 73 (70.2%) regularly practiced various sports (FSSI group), 31 (29.8%) never practiced physical activity, or practiced irregularly (ENS group).An additional group examined was the Italian national deaf female volleyball team (TEAM volley group) which was the silver medal at the 2018 Paralympics and the 2019 European Championship.The group is composed by 15 athletes with an average age of 22.7 years old (SD 3.99). In this group the cause of deafness is hereditary in 7 cases (46.7%), unknown in 5 (33.3%), and viral in 3 (20%).Hearing loss originated at birth in 12 cases (80%), within the first few months in 2 (13.3%) and within 3 years in one case (6.7%). Three athletes had a cochlear implant. Only one athlete had had vertigo.Thanks to the translation of sign language, every individual was adequately and preemptively instructed on the tests they would being subject to, for both the methods and the scope of the test.The occurrence of a vestibular deficit was evaluated through the Video Head Impulse Test (v-IHT) ,31,32. T2) irregularly positioned on a wooden board (23 × 28 cm2). The experimenter points to a series of blocks at a rate of one block per second. Subsequently, the participant is required to point to the same blocks in their order of presentation. The length of the block sequences (starting from 2-block sequences) increases by one item until recall is no longer correct. The procedure ends when the number of wrong reproductions exceeds the proportion of admissible errors per length. A span score was calculated corresponding to the larger sequence the subject can correctly reproduce. The maximum score possible is 9.The single most important nonverbal task for the assessment of visuo-spatial working memory (VSWM) is the Corsi block tapping task (CBTT), also known as the Corsi Span Test. It also involves spatial attention. The traditional version of Corsi apparatus consists of a set of nine identical blocks  and it is significantly impaired in patients suffering from chronic peripheral vestibular hypofunction when compared with healthy controls ,10.It was also used in sports athletes with a history of concussion .We used the digital version of Corsi’s test (eCorsi test) ,35 Figu.In Corsi block-tapping task for digital tablets (eCorsi), instead of cubes to be tapped on a board, the setup consists of squares that flash on a computer screen. Participants reproduce the sequences by tapping blocks on a (touch) screen, without substantial differences between the two versions in terms of performance.In addition, in the eCorsi test, the final score corresponds to the maximum number of targets reproduced correctly and therefore ranges from a minimum of 2 to a maximum of 9.430 subjects without vestibular deficits and hearing loss (NORM); 224 females (52.1%) and 206 M (47.9%), 300 aged 17 to 64 years  and 130 aged 65 years or more .404 subjects with chronical vestibular failure (CVF group); 210 females (51.9) and 194 males (48.1%), 234 aged 17 to 64 years  and 170 aged 65 years or more .34 subjects without vestibular deficits and hearing loss who practice volleyball, basketball and football at an amateur level (SPORT group); 14 females and 31 males, with an average age of 25.44 years (SD 4.63).50 professional athletes (PROF group) in basketball, volleyball, motorsport; 15 females and 35 males, with an average age of 23.94 years (SD 3.46) without vestibular deficits and hearing loss18 females NORM who do not practice sport (NORM NS group) and 25 who often practice volleyball (NORM V group) at a professional level on par with the Italian national deaf volleyball team, without vestibular deficits and hearing loss. The average age was equivalent to the TEAM volley’s group.The data was confronted with the following:Statistical analysis was performed by Statistical Package for Social Science (SPSS).t-test. A paired sample t-test was performed to assess the differences in the same subject, while an independent sample t-test was used to compare two groups. Differences with a p-value < 0.05 were considered statistically significant.Groups were tested for normality. The difference between the means of normally distributed variables was calculated using Student’s A bilateral vestibular deficit was present in 66 subjects  and in 38  it was either absent or non-significant.In 31.8% of subjects with vestibular deficit, vertigo was present in the medical history and in 28.2% of subjects without a clear vestibular deficit. Therefore, all cases are to be considered in a state of good vestibular system adaptability.p < 0.0001), as shown in p = 0.0734) [Both CVF and ENS have a statistically lower score than NORM ( 0.0734) .p = 0.6921).In ENS, the presence of a vestibular deficit does not significantly change the score (p = 0.0009).ENS have a better score than CVF (p = 0.9113).ENS NS have an equivalent score to the CVF group (p = 0.0928).FSSI score does not differ from the NORM group (t-test: p < 0.0001).ENS NS have a significantly lower score than NORM (t-test: p < 0.0928).FSSI have score values equivalent to those of NORM (p = 0.0026) and is significant between the ENS itself and CVF (p = 0.0154) and between CVF and NORM (p < 0.0001).In subjects over 65, the difference between ENS and NORM is lower (p = 0.0130).FSSI have a significantly better score than NORM for the same age (p = 0.0005).The comparison between the score of 34 SPORT and 34 FSSI with the same athletic skill level shows  a non-siThe score of both groups is lower than that of the PROF group. The comparison between SPORT and PROF, with not quite statistically significant age difference, confirmed a statistically better performance in PROF.In the group containing the 15 athletes of the Italian national deaf volleyball team (TEAM volley group), eight had a vestibular deficit, four unilateral and four bilateral.t-test: p < 0.0011) in those who practice sport rather than those who do not; the athletes of the national team have a score equivalent to the score of the athletes with normal hearing (t-test: p = 0.8857).In comparison , 18 subjIn the totality of ENS and TEAM volley, there is a small but significant male advantage .p = 0.4641).However, the difference is inferior to the one observed in NORM . CompariIn CVF, the difference is not significant .The subjects suffering from chronic hearing loss and/or unilateral or bilateral vestibular deficit have shown a VSWM less efficient than that of the NORM group.The contemporaneous presence of these two deficits does not seem to significantly change this cognitive function.However, on average, ENS have a better score than CVF; this hints at a better adaptive strategy, likely supported by a cross-model plasticity which includes the regular use of lipreading .This characteristic occurs mainly in subjects who practice sport: their VSWM is equivalent to NORM’s, or even better for subjects in the over 65 age group.The effect of physical activity is undeniable for the same athletic skill level; the performance difference with respect to NORM vanishes for amateurs and professional athletes.Therefore, it appears to be confirmed that motor skill learning induces some differences in brain network plasticity regarding non-active peers ,37,38.The comparison between males and females reveals a small but significant male advantage on average, as it was often observed in VSWM tests ,39,40 afHowever, the difference is lower than the one found in the NORM, so the likely influence of similar adaptive strategies between the two genders in day-to-day life is confirmed.Indeed, the difference between genders vanishes completely if we compare the score of TEAM volley and the score of 34 FSSI at the same athletic skill level. This is most likely the effect of a similar and prolonged training.Indeed, the sex difference in human SWM can be attributed to the complexity of the variables involved in the visuo-spatial domain, and can be better explained by differences in spatial competences. This could reflect the use of different strategies, rather than different competences, in both sexes.We have already demonstrated how vestibular rehabilitation is capable of significantly improving the spatial memory of subjects suffering from monolateral or bilateral vestibular deficit.The study underlines that physical activity, when practiced regularly, allows the same results to be achieved in subjects with profound hearing loss, regardless of vestibular deficit, where VSWM is lower on average than healthy peers.The study shows that, in both genders, physical activity improves these cognitive functions ,41,42, pThus, it is clear that, in patients with this deficit since infancy, it is suggested to support and recommend physical activity.When the patient is a newborn, we suggest stimulating the vestibular and cognitive function throughout daily exercises such as “hide and seek”, walking, and flips from 18 months old ,44.Indeed, in this way, the newborn can develop spatial-temporal reasoning, a sense of direction, saccadic spatial exploration and motor coordination. Physical activity activates different neural networks compared to a sedentary life; this promotes the development of new cognitive strategies characterized by better spatial-temporal reasoning and navigation skills, which are useful in a person’s social life, in particular in sport and driving ,46.


Older adults who live alone and have difficulties in activities of daily living (ADLs) may have been more vulnerable during the COVID-19 pandemic. However, little is known about pandemic-related changes in ADL assistance  and its international variation. We examined international patterns and changes in provision of ADL assistance, and related these to country-level measures including national income and health service expenditure.We analysed data covering 29 countries from three longitudinal cohort studies . Eligible people were aged ≥50 years and living alone. Outcomes included ADL difficulty status  and receipt of ADL assistance. Wealth-related inequality and need-related inequity in ADL assistance were measured using Erreygers’ corrected concentration index (ECI). Correlations were estimated between prevalence/inequality/inequity in ADL assistance and national health-related indicators. We hypothesized these measures would be associated with health system factors such as affordability and availability of ADL assistance, as well as active ageing awareness.During COVID-19, 18.4% of older adults living alone reported ADL difficulties (ranging from 8.8% in Switzerland to 29.2% in the USA) and 56.8% of those reporting difficulties received ADL assistance (ranging from 38.7% in the UK to 79.8% in Lithuania). Females were more likely to receive ADL assistance than males in 16/29 countries; the sex gap increased further during the pandemic. Wealth-related ECIs indicated socioeconomic equality in ADL assistance within 24/39 countries before the pandemic, and significant favouring of the less wealthy in 18/29 countries during the pandemic. Needs-related ECIs indicated less equity in assistance with ADLs during the pandemic than before. Our hypotheses on the association between ADL provision measures and health system factors were confirmed before COVID-19, but unexpectedly disconfirmed during COVID-19.This study revealed an unequal  response from countries to older adults living alone during the COVID-19 pandemic. The findings might inform future research about, and policies for, older adults living alone, particularly regarding social protection responses during crises.The online version contains supplementary material available at 10.1186/s12877-022-02799-w. Public health measures such as social isolation and lockdown are effective in containing the spread of COVID-19. However, a resultant reduction in social contact outside the household might marginalize older adults who live alone. These people may be at greater risk for adverse health outcomes than those living with others during the pandemic, because of less direct support and potentially lesser access to essential health and daily services . Their vAssistance with daily living, such as via domiciliary (home) care, is often essential for adults living alone with ADL difficulties, perhaps especially during a crisis. There is considerable international variation in models of domiciliary care provision, and its funding , 9. Sex The objective of this study was to estimate the prevalence of older adults having difficulty in ADLs; their receipt of ADL assistance; variations in the provision of ADL assistance in terms of inequality  and inequity (disparity by need); international variation in these measures; and the impact of COVID-19 pandemic on these factors. We also examined health system factors, such as affordability and availability of ADL assistance, and active ageing awareness, which might predict these variables.We used publicly available data from three cohort studies collecting relevant self-report data for older adults: 1) the English Longitudinal Study of Ageing (ELSA) in the UK , 2) the Importantly, these studies ran during 2020. Each participant completed a standardised questionnaire, face-to-face (HRS) or via internet/telephone assessments , described elsewhere –16, 21. We used data from the most two recent survey waves . Eligible people were those aged ≥50 who lived alone.The first outcome was ADL difficulty status, in relation to six basic ADLs  and five instrumental ADLs  –24. EachThe secondary outcome was receipt of assistance with ADLs. The questions used varied slightly across cohort/wave but covered the same domains as difficulty status. We used a binary indicator (yes/no) for receipt of ADL assistance. See Although both outcomes were calculated from self-reported data, such measures of physical functioning have been evaluated in HRS and HRS-family studies .For each country, we also obtained the following measures: (1) gross national income per capita; (2) public expenditure on health as a proportion of GDP; (3) the number of formal long-term care (LTC) workers offering personal care per 100 population aged ≥65; (4) LTC workers offering nursing care per 100 population aged ≥65; (5) informal LTC workforce, reflected by the percentage of the population volunteering to provide ADL help for people outside their own household; and (6) active ageing index (AAI), a United Nations index to monitor national progress on “active ageing”, where higher scores are better . Data onThe data were publicly available. The use of public secondary de-identified data made the present study exempt from institutional review board review. Participants in the original studies gave informed consent and each study was approved by a relevant ethics body: for ELSA, the UK Health Research Authority South Central Berkshire Research Ethics Committee , 18; forData were analysed by country. Survey weighting per wave was used to account for sampling design  and study attrition.To estimate sex disparity, and any mediating effect of the COVID-19 pandemic on sex disparity, among those receiving ADL assistance, we fitted country-specific weighted logistic regression models. The dependent variable was receipt of ADL assistance. Predictors were: age (continuous), sex , wealth  for each survey wave by country, taking receipt of ADL assistance as the outcome variable and wealth as the reference variable, following World Bank guidelines . This in2 by linear regression to establish the proportion of variance explained by each predictor. We hypothesised that increasing welfare support in a country would be associated with a greater receipt of ADL assistance and greater equality/equity in such receipt.We related receipt of ADL assistance, wealth-related ECI, and need-related ECI to six measures for each country (described above) relating to the affordability and availability of ADLs assistance, as well as active ageing awareness—collectively referred to as welfare levels. e adopted Kendall’s rank correlation coefficient  to measure the strength and direction of the association between each of these variables and the proportion receiving ADL assistance, and wealth- or need-related ECI. We calculated RMissing data were imputed. For wealth, we used multiple imputations with chained equations and generated five imputed data sets to reduce bias and maintain power . For “heWe performed a structural sensitivity analysis. To eliminate the possible influence of different questionnaires used by the three cohorts, we repeated the analysis including only SHARE data.P values and 95% confidence intervals (CIs) throughout. P < .05 was considered statistically significant. Results are reported following the STROBE checklist for cohort studies.Analyses used R version 3.6.0. We report two-tailed A total of 15,648 individuals were included in the survey waves after the COVID-19 outbreak, and 28,137 individuals before COVID-19 as a comparison group. More than 70% of older adults living alone were female . Before the pandemic, across all countries included, 27% of older adults living alone reported ADL difficulties  and 51.5% of those reporting difficulties received help with ADLs (ranging from 6.2% in Romania to 85.1% in the Netherlands). During the pandemic, 19.6% of older adults living alone reported ADL difficulties (ranging from 8.8% in Switzerland to 28.5% in the USA) and 56.3% of those reporting difficulties received help with ADLs (ranging from 25.5% in Israel to 77.1% in Greece); see Table Figure Standardized wealth-related and need-related ECIs for receipt of ADL assistance are shown in Fig. p = 0.0005, R2 = 0.42), AAI , public expenditure on health , and percentage of the population volunteering to provide ADL support . After the COVID-19 pandemic began, it was negatively associated with AAI , and not other variables , AAI , the LTC workforce for personal care , and volunteering  , AAI , and volunteering . In contrast, during COVID-19, none of the six country-level resource measures were correlated with need-related ECI , and in many countries this sex effect increased during COVID-19. The distribution of ADL assistance shifted towards less wealthy people but also towards people with slightly fewer needs. Provision of ADL assistance was positively associated with national welfare indicators before COVID-19, and likewise for need-based equity/inequity in ADL assistance, but these associations disappeared. Wealth-based equality/inequality in assistance was not associated with welfare indicators before COVID-19, but this association became positive. Overall, this study revealed a variability in countries’ ability to provide support for older adults living alone during the pandemic.Compared with the pre-pandemic period, fewer older adults living alone reported ADL difficulties during the pandemic Table . This miFemales were more likely to receive ADL assistance than males in 16/29 countries, even after controlling for age, wealth, and the extent of difficulty. There have been similar finding from Japan  and the Our hypotheses regarding socioeconomic equality and equity in receiving ADL assistance were confirmed for the period before the pandemic, but disconfirmed during the pandemic. During the pandemic, ADL assistance was provided more to those of lower wealth status (in 19/29 countries)  is notable as a factor that might be changed rapidly in the short term, and it did increase during COVID-19, particularly in countries with a relatively low level of welfare provision . In this study, we took the value before the pandemic as a reference to examine how equity changed. Fourth, volunteering is a potential modifiable factor identified in this study, but its influence could be underestimated, as the percentage of the population volunteering to provide ADL assistance was calculated from cohorts surveying people aged ≥50, and not all populations. Fifth, individuals’ difficulty status in the UK was matched to their data collected in 2018, not 2020; this could bias UK results, but is unlikely to have influenced our general conclusions, borne out by consistent sensitivity analyses. Sixth, other factors, such as education or other social determinants of health, might mediate the relationship between ADL impairment and seeking or obtaining assistance but were not examined in the current study. Seventh, we examined the situation country by country, but only limited national-level factors were explored. In addition, for many countries only limited data on formal long-term care workforce were available.There was an unequal international response in the provision of ADL support to older adults living alone during the COVID-19 pandemic, with evidence suggesting under-provision of support to many. The proportion of the elderly population living alone is expected to increase, as our societies face an ageing trend, and countries should consider their future preparedness to provide support to vulnerable individuals during times of crisis as well as normality.Additional file 1: Supplementary Methods. Questions used in data collection, formula to calculate the (Erreygers’ corrected) concentration index, and measures of wealth status. Supplementary Table 1. Testing the influence of the COVID-19 pandemic on the association between national level factors and outcomes of interest. Supplementary Figures 1-3. Sensitivity analyses, with conventions as for Figs. Supplementary Figure 4. Change in the percentage of population volunteering to provide ADL support against change in the percentage of people receiving assistance with ADLs.


IntroductionAsymmetric sensorineural hearing loss is the main early symptom of retrocochlear lesions, hence its importance in screening for vestibular schwannomas. Currently, there is no consensus regarding its definition. The objective was to identify the audiometric pattern that would serve as a predictor for vestibular schwannoma in patients with asymmetric hearing loss.Materials and methodsA cross-sectional study was conducted that included patients with asymmetric hearing loss attending a secondary care center and a tertiary care center. Clinical, audiometric and imaging (MRI with gadolinium) variables were collected. Asymmetric hearing loss was defined as a difference of 15 dB in one or more frequencies between both ears. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of different audiometric patterns were analyzed.ResultsA total of 107 patients were studied and divided into two groups: group 1 without vestibular schwannoma (n=98); and group 2 with vestibular schwannoma (n=9). No significant difference in demographic characteristics or audiometric patterns was found in patients with and without vestibular schwannoma. The audiometric pattern with the best sensitivity as a screening test was a difference >20 dB in the 4,000 Hz frequency, with a sensitivity of 77.78%, specificity of 30.61%, PPV of 8.33%, NPV of 93.75% and accuracy of 34.50%.ConclusionThe audiometric pattern with the best results was a difference >20 dB in the 4,000 Hz frequency range; however, patients with asymmetric hearing loss could not be differentiated from patients with retrocochlear lesions based only on audiometry. Asymmetrical hearing loss must be studied with MRI. Asymmetric hearing loss is a difference in hearing loss between both ears, in which the contralateral ear might also be affected. Although hearing loss is the third most frequent cause of disability in some countries , there iFurthermore, simple audiometry could be a potential early indicator of vestibular schwannoma (VS), becoming a simple and cost-effective tool for the screening of these tumors.It is estimated that 2%-8% of patients with asymmetric hearing loss have retrocochlear lesions , this syAsymmetric sensorineural hearing loss can be caused by damage to the cochlear hair cells, retrocochlear lesions and even cortical hearing loss. Additionally, we should consider cochlear nerve disease such as that produced by pontocerebellar angle lesions which can include meningiomas, petrous apex cholesteatomas, multiple sclerosis and, more commonly, VSs; this latter pathology causes mechanical compression of the cochlear nerve . The incVSs or acoustic neurinomas are benign, slow-growing tumors arising from the eighth cranial nerve. They are the most common tumors of the pontocerebellar angle and represent 6%-10% of intracranial tumors [Actually, the main symptom of VS is sensorineural hearing loss which is usually asymmetric, gradual and high-tone hearing loss with greater asymmetry in the frequency range of 2-8 kHz .The mechanism by which a VS causes hearing loss may not be attributed only to its size but are related to biomarkers, such as perilymph proteins and other specific subtypes of heat shock protein 70 (HSP70) .Approximately 50% to 60% of VSs lead to gradual or abrupt hearing loss at high frequencies, with only 4% to 26% of patients presenting sudden hearing loss . Gadolinium-enhanced nuclear magnetic resonance imaging (MRI) is the current diagnostic gold standard for retrocochlear lesions ,21. HoweThe ideal screening test should be accurate and inexpensive, but to date, such a test does not exist in the initial diagnosis of schwannomas . HoweverIn our study, we sought to determine the audiometric pattern to be used as a screening test for VS.The study design was a cross-sectional study. The location was multicenter. Consecutive patients were included from March 2009 to December 2010 at a tertiary care center and April 2016 to August 2018 at a secondary care center in a single otolaryngology clinic.SubjectsThe inclusion criteria were patients who attended the otorhinolaryngology service of a secondary care center and a tertiary care center with a diagnosis of asymmetric hearing loss by audiometry, defined as a difference of 15 dB in one or more frequencies between ears. After a diagnosis of asymmetric hearing loss, MRI was indicated. Only patients with MRI examinations were included.The exclusion criteria were patients who did not consent to participate, patients with hearing loss of conductive origin, patients with retrocochlear lesions other than VSs, and patients with previous pontocerebellar angle surgery.The elimination criteria were patients who had an incomplete audiometric study and/or absence of MRI.Data on age, sex, tinnitus, vertigo, exposure to ototoxic drugs, trauma, ear surgery, noise exposure, stapedial reflexes, evoked potentials, MRI, otoacoustic emissions, and asymmetric hearing loss were collected.Once the diagnosis of MRI was obtained, patients were ultimately compared and categorized into two groups: group 1 without VS (WOVS) and group 2 with VS (WVS). Clinical and demographic characteristics were described for Group 1 (WOVS) and Group 2 (WVS).Definition of hearing lossThis study analyzed all possible definitions of asymmetric hearing loss and the most inclusive definition was chosen: a difference of 15 dB in one or more frequencies between ears.All definitions available in the literature of asymmetric hearing loss were analyzed -15. CalcStatistical analysis2 test for categorical variables and Student’s t-test for continuous variables.The data were analyzed with the SPSS statistical package, version 21.0 . Descriptive statistics were used with measures of central tendency and dispersion according to the distribution of the data. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio, negative likelihood ratio and accuracy were calculated. The data were compared using the χThe definitions of asymmetric hearing loss described in the literature -15, wereA total of 107 patients were included; 1 patient was excluded due to meningioma. Thus, 107 patients were ultimately included: group 1, without VS (WOVS) n=98 (91.6%) and group 2, with nine patients with VS (WVS) (8.4%).Basal demographic characteristics were collected Table  and analIn our study, we observed that the left ear was more frequently affected in both groups . Progressive hearing loss was also a prevalent clinical feature in both groups . The duration of hearing loss progression was 45.3 in group 1 vs. 47.11 months in group 2 (p=0.644). The absence of vertigo was 55.6% vs. 34.7%; (p=0.21), respectively.Tinnitus was present in most patients, documented in 94.8% (n=92) of group 1 and 100% (n=9) of group 2, with no significant difference between the groups (p=0.45). However, 100% of the patients with bilateral tinnitus belonged to group 1.The causes of facial mobility disorders observed in group 1 (WOVS) were as follows: Bell’s facial paralysis (n=6), recurrent facial paralysis (n=1), Melkersson-Rosenthal syndrome (n=1), demyelinating disease (n=1) and idiopathic (n=1). The only case of facial mobility disorder documented in group 2 (WVS) occurred in a patient with schwannoma and a history of facial paralysis one year prior to diagnosis.An abnormal otoscopy was documented in 6 cases, in order of frequency: due to myringosclerosis (n=2), opaque membrane (n=2), tympanic graft (n=1) and an external auditory canal osteoma (n=1).As part of their diagnostic protocol, some patients underwent neuro-otological tests, the results of which were not significantly different between the two groups, except for auditory brainstem response p ≤ 0.001), nevertheless the sample is small  curve Figure , two audIn summary, the pattern that showed the best result -as a screening test- was the 4,000 Hz rule, with a sensitivity of 77.78%, specificity of 30.61%, PPV of 9.33%, NPV of 93.75%, and accuracy of 34.58%.In our study, no significant difference in demographic characteristics or audiometric patterns was found in patients with and without VS. This study represents a cross-sectional and multicenter study of asymmetrical hearing loss patients. There are multiple definitions of asymmetrical hearing loss to date Table . Only niAccording to our results, the clinical characteristics  did not allow us to identify patients with VS.Tinnitus had a similar prevalence in both groups (p=0.322), interestingly, patients with VS presented with only unilateral tinnitus. Several studies have emphasized the importance of unilateral tinnitus for the diagnosis of retrocochlear lesions . In contAudiometry is considered a simple, economic, and easily available test without adverse effects, allowing us to consider it as an optimal screening test. This study had the aim to test all available definitions of asymmetric hearing loss in the literature, therefore, asymmetry ≥15 dB at any frequency was considered as an inclusion criterion; this definition could encompass all of the other definitions of asymmetric hearing loss. This definition has also been used as an inclusion criterion in previous studies ,24. HighThe sensitivity, specificity, PPV and NPV of each of the definitions and frequencies were calculated, with the best performance found for asymmetry ≥20 dB at the 4,000 Hz frequency, which was better than the other definitions proposed in the literature.Regarding the diagnostic algorithms of VSs, Saliba et al.  proposedA study conducted in Denmark by Gimsing  calculatSimilarly, Obholzer et al.  performeOur results had low sensitivity and specificity in all the parameters studied. It is necessary to emphasize that the most relevant studies comparing the audiometry of patients with and without tumors were performed retrospectively based on MRI. These former studies were not prospective studies but case-control studies. This fact explains the paradoxical normal hearing in their control groups ,23. In cUnlike what has been described in another study that included asymmetry ≥15 dB in its logistic regression model as an independent predictor variable of the presence of VS , in our Strengths of this study rely on the multiple analysis of all the asymmetric hearing loss definitions available in the literature; additionally, we studied each frequency and its respective asymmetries. Since the audiometry did not show an adequate performance as a screening test, it relies on us, the clinicians, to indicate the MRI in any case of suspicion; nevertheless, the best definition in this study was the Rule of 4000.It is important to consider these results since an undiagnosed schwannoma misses the possibility of being submitted on time to a procedure (radio-neurosurgery or neurosurgery) to preserve hearing and increase the quality of life of our patients.The most recent study on MRI and asymmetric hearing loss, included 1059 patients, among those patients, there were only 16 patients with VS. The authors performed equally an analysis with the different definitions of asymmetric hearing loss. Overall, their results are similar to ours, but our sensitivity is lower since none of the definitions reached 100%. Additionally, the proportion of VS patients in Bhargava study is much lower than ours; which is explained due to the reduced incidence of the disease. Cross-sectional studies tend to have scant VS patients. The main limitation of this study is the low number of patients with VS; nonetheless, the occurrence of VS is 2%-8%  in patieTill today, the MRI is the gold standard in the study of asymmetric hearing loss.Patients seen at a neurotology and otolaryngology center with asymmetric hearing loss could not be differentiated from patients with retrocochlear lesions based on audiometry alone. No significant difference in demographic characteristics or audiometric patterns was found in patients with and without VS. Clinical suspicion is recommended if there is asymmetry of at least 20 dB in the 4,000 Hz frequency. Asymmetrical hearing loss must be studied with MRI. More studies are needed to corroborate our results.


Prenatal infections can have adverse effects on an infant's hearing, speech, and language development. Congenital cytomegalovirus (CMV) and human immunodeficiency virus (HIV) are two such infections that may lead to these complications, especially when left untreated. CMV is commonly associated with sensorineural hearing loss in children, and it can also be associated with anatomical abnormalities in the central nervous system responsible for speech, language, and intellectual acquisition. In terms of speech, language, and hearing, HIV is most associated with conductive and/or sensorineural hearing loss and expressive language deficits. Children born with these infections may benefit from cochlear implantation for severe to profound sensorineural hearing losses and/or speech therapy for speech/language deficits. CMV and HIV simultaneously present in infants has not been thoroughly studied, but one may hypothesize these speech, language, and hearing deficits to be present with potentially higher severity. Early identification of the infection in combination with early intervention strategies yields better results for these children than no identification or intervention. The purpose of this review was to investigate how congenital CMV and/or HIV may affect hearing, speech, and language development in children, and the importance of early identification for these populations. These include rubella, Zika virus, lymphocytic choriomeningitis virus (LCMV), herpes simplex virus (HSV) types 1 and 2, measles, varicella zoster virus, mumps, and West Nile virus  and their relationship to hearing loss and speech/language delays in infants. The following four search strategies were utilized to obtain all of the sources for this paper, as listed below:* OR pediatric*) AND (hearing loss OR speech OR language) AND  AND (magnetic resonance imaging OR MRI)* OR pediatric*)(HIV) AND (hearing loss OR speech OR language) AND (child* OR neuropath* OR otolog* OR cerebrum) AND , published in English, full text, human subject, and journal articles. The following age filters were also applied: child (birth-18 years), infant (birth-23 months), infant (1–23 months), newborn (birth-1 month), and preschool children (2–5 years). Search strategy 4 did not include these age filters in order to find detailed information pertaining to general HIV infection on anatomical structures. Specific search strategy information is described in Researchers have investigated how congenital CMV (cCMV)  is passeHowever, universal CMV testing is not commonplace in the American healthcare system, usually being implemented only when there is speculation of other viruses, such as mononucleosis . One sucIf a fetus contracts CMV while in the womb, they are said to have cCMV; if they contract CMV shortly after birth, they are said to have postnatal CMV. These CMV acquisition factors should be considered when discussing the relationship between CMV and hearing loss. Of the children infected with cCMV, 90% present as asymptomatic; this percentage is likely to increase if an increased capacity for cCMV screenings in hospitals for all newborns becomes available and implemented . Ten perEven if a child with cCMV is born with normal hearing, a progressive SNHL can occur later in life and have adverse effects on speech development. For example, Fletcher et al.  found a Other researchers have investigated the severity of SNHL associated with CMV. Lanzieri et al.  studied As previously noted in other texts , 29, preSome researchers have also studied how medical treatment of cCMV affects the development of the auditory system. Rosenthal et al.  collecteSince speech and language development may also be limited for children with delayed physical, intellectual, and motor development, researchers have evaluated how cCMV affects these developmental milestones for this population. Lopez et al.  comparedIn addition, De Kegel et al.  examinedConsidering the importance of speech and language development in early childhood, utilizing cochlear implants (CIs) for children with cCMV-related hearing loss is an option to mitigate the effects of decreased auditory input necessary for speech understanding. Corazzi et al.  comparedMRI can also be an important diagnostic tool when determining course of treatment for a child. Diogo et al.  describeCannie et al.  found acOverall, cCMV is one of the most common prenatal infections causing hearing loss in a developing fetus. Whether hearing loss is present at birth or develops over time, the implications on speech and language development are evident. Since the virus also affects physical, intellectual, and motor development, care should be taken when evaluating and intervening for this population; there may be irreversible structural and functional damage to the brain that limits the benefits of CI surgery for some individuals.HIV is a retrovirus that attacks a person's immune system. HIV-infected cells attack helper T-cells, which are crucial for developing a strong immune system, thus leaving the person immunocompromised and more susceptible to other infections  Table 2Table 2. in-utero , which are a measure of the function of the outer hair cells within the cochlea, has been mixed. In addition to finding higher prevalence of middle ear disorders, Maro et al.  found HIIn addition to its effects on the peripheral auditory system, HIV can also affect the functionality of the central auditory nervous system. Rarey  discoverPrevious research has highlighted a common trend of deteriorated language development for prenatal HIV-infected children and prenatal HIV-exposed but uninfected children. Alcock et al.  examinedin-utero antiretroviral therapy  for this population and its effect on speech and language development. They estimated the prevalence of language impairment to be 15%, but this prevalence was greatly reduced when the infant was exposed to ART in-utero. However, the risk for speech impairment was not elevated for this population. Similarly, Rice et al.  responsible for speech and language development. Through neuroimaging techniques, DeCarlie et al.  found chHIV can also interfere with typical cognitive, motor and neurodevelopment, all of which are crucial for speech and language development. In a sample of 35 HIV-infected preschoolers and 35 HIV-exposed preschoolers in the Democratic Republic of Congo, Van Rie et al.  found a Some research has considered how medical treatment of HIV impacts the duration of neurological developmental delays. Brahmbhatt et al.  studied While there is limited research on how CIs or hearing aids assist children with HIV-related hearing loss, fitting this population with assistive listening technologies may be challenging. Since children with HIV typically present with conductive hearing losses  more often than sensorineural, it may be difficult for these children to wear hearing aids due to inflammation, pain, and drainage in the external auditory meatus. For those with sensorineural hearing loss, CI surgery can be very risky because HIV greatly weakens a person's immune system; CI surgery can introduce other infections into the inner ear space, possibly leading to more serious complications. Therefore, Cohen et al.  recommenOverall, HIV can have life-threatening implications due to increased risk of contracting other diseases. If not recognized at birth, hearing, motor, cognitive, and language development can be delayed or limited as the disease progresses. While hearing loss and speech developmental delays are not the most pressing concerns for this population, they are important elements of a child's quality of life that should also be considered.in utero” HIV infection, suggesting a relatively high rate of CMV infection in HIV-exposed infants. Purswani et al. (There has been limited research on the effects of CMV and HIV together on speech, language, and hearing development . A poteni et al.  studied It is unclear how the combination of cCMV and HIV affect hearing, speech, and language development for these children. One may hypothesize since each disease independently may affect these developments, the combination of these diseases may result in more severe delays and abnormalities. More research is needed to specifically quantify these effects on hearing, speech, and language development, but individuals should consider early identification and treatment of these diseases to mitigate the potentially negative effects of having both infections simultaneously.Both cCMV and congenital HIV can adversely affect a child's hearing, speech, and language development. These infections can create structural and functional anomalies in the peripheral and central auditory systems, as well as the central nervous system, which may limit the benefits of CI and hearing aid fittings. MRI and other neuroimaging techniques can be helpful in diagnosing and treating hearing loss in a child with one of these diseases by determining whether they would be a good candidate for hearing devices based on anatomical findings. Although CI surgery generally presents risk for patients, this risk may be amplified for children with cCMV and HIV due to their weakened immune systems. Speech and language therapy may also be warranted for children with notable speech and language performance deviations.One of the best methods for limiting the devastating effects of cCMV and HIV is early identification. If pregnant mothers are screened early in pregnancy for CMV and HIV, adequate medical treatment options can be readily available for their developing babies and themselves. Since these infections can be life-threatening, hearing and speech development may be one of the last concerns these families and healthcare providers have for the child. However, if the child is in a stable condition and progressing well medically, aiding the hearing loss and offering speech and language therapy may greatly improve the child's quality of life.All authors reviewed the papers, analyzed the data, wrote the article, and discussed the results at all states.This work was supported by an internal funding source from the UF College of Public Health and Health Professions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Bacteroides, Prevotella, and Escherichia/Shigella, and further species-level and network analyses identified certain potential keystone taxa in each group. Some of the dominant species, such as Prevotella copri, Bacteroides dorei, and Bacteroides vulgatus, could be responsible for causing colorectal diseases. The SMS data recovered diverse antibiotic resistance genes of tetracycline, macrolide, and beta-lactam, which could be a result of antibiotic overuse. This study explored the gut microbiota of patients with three different types of colorectal diseases, and the microbial diversity results obtained from 16S rRNA amplicon sequencing and SMS data were found to be similar. However, the findings of this study are based on a limited sample size, which warrants further large-scale studies. The recovery of gut microbiota profiles in patients with colorectal diseases could be beneficial for future diagnosis and treatment with modulation of the gut microbiota. Moreover, SMS data can provide accurate species- and gene-level information, and it is economical. It can therefore be widely applied in future clinical metagenomic studies.The gastrointestinal tract, the largest human microbial reservoir, is highly dynamic. The gut microbes play essential roles in causing colorectal diseases. In the present study, we explored potential keystone taxa during the development of colorectal diseases in central China. Fecal samples of some patients were collected and were allocated to the adenoma (Group A), colorectal cancer (Group C), and hemorrhoid (Group H) groups. The 16S rRNA amplicon and shallow metagenomic sequencing (SMS) strategies were used to recover the gut microbiota. Microbial diversities obtained from 16S rRNA amplicon and SMS data were similar. Group C had the highest diversity, although no significant difference in diversity was observed among the groups. The most dominant phyla in the gut microbiota of patients with colorectal diseases were Bacteroidetes, Firmicutes, and Proteobacteria, accounting for >95% of microbes in the samples. The most abundant genera in the samples were  According to global cancer statistics 2020 by GLOBOCAN, among the 36 kinds of cancers, colorectal cancer is the third most common malignancy and the second most lethal tumor in 185 countries . It is aFusobacterium nucleatum , Group C , or Group H . Approximately 500 µL of the fecal sample from each tube was used for DNA extraction. The DNA was quantified using Nanodrop 2000 , and the V3-V4 regions of the 16S rRNA gene sequences were amplified using KAPA HiFi HotStart ReadyMix PCR Kit KK2600 , according to the manufacturer’s instructions. The amplified PCR fragments were purified and mixed . The seqp value was significant at 0.05, and the critical r-value cutoff was 0.7 . KAPA HyperPrep Kit , KAPA Dual-Indexed Adapters (KK8722), KAPA pure beads, and KAPA Library Quantification Kit (KK4824) were used to construct the SMS library . The SMSThe quality of raw SMS data was evaluated using FastqQC (version 0.11.9), and adaptor sequences in raw reads were removed using Trimmomatic  was higher than in Group C (0.4 ± 0.77%) and Group H  in the groups (Compared with 16S rRNA gene amplicon data, SMS data can provide species-level information. Based on SMS data, the most dominant species were assigned to s genera . The perl cancer . The perectively . The F. e groups , suggeste groups . The mice groups . Most mie groups .The beta-diversity analyses based on both 16S rRNA and SMS data revealed that samples from Groups A, C, and H overlapped with each other, with no significant difference . The UPGThe network analysis can indicate potential microbes associated with the disease, and keystone taxa can be predicted based on the microbiota data . The mosThe nodes in all these networks were assigned to Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Fusobacteria. In Group A, the most dominant OTUs demonstrated positive correlations with other OTUs. Only four OTUs, namely ZOTU_13, ZOTU_1, ZOTU_61, and ZOTU_58, demonstrated a negative correlation with other OTUs . These fThe assembly of SMS data generated large amounts of contigs. The assembly quality was related to the generated data. The contig N50 of all the samples ranged from 2,352 to 9,593 bp . The larColorectal cancer is the third most common cancer and the second leading cause of cancer-related mortality, which suggests the importance of investigating the molecular mechanisms of colorectal carcinogenesis . EnvironF. nucleatum, were low (Microbial profiling revealed higher diversity in Group C than in other groups, which is consistent with previous results that indicated higher microbiota diversity in patients with colorectal cancer than in healthy individuals . The difwere low . Differewere low . Therefowere low . In futuwere low . Moreovewere low .K. pneumoniae and S. pasteurianus, in the samples revealed the potential of microbial analyses to recognize infective microbes in patients (Prevotella and other gut microbes can be identified in oral microbiota (The gut microbiota is affected by diet and other environmental factors . The funpatients . Diversepatients . Prevotecrobiota , and thecrobiota . Therefocrobiota . Moreovecrobiota .The metagenomic strategy had been widely used to identify keystone taxa in human microbiome . The metIn this study, we recovered gut microbiota from patients with three different colorectal diseases and identified the potential keystone taxa. In addition to pathogenic microbes in a few adenoma disease samples, certain passenger microbes could have roles in causing colorectal diseases. The 16S rRNA gene amplicon and SMS data provide similar alpha- and beta-diversity results, and SMS data may be applied for future clinical use in colorectal diseases. In future, designing an appropriate diet to modulate the gut microbiota may be beneficial for the prevention or treatment of colorectal diseases.


Obsessive compulsive disorder (OCD) is associated with disruption of sensorimotor gating, which may contribute to difficulties inhibiting intrusive thoughts and compulsive rituals. Neural mechanisms underlying these disturbances are unclear; however, striatal dopamine is implicated in regulation of sensorimotor gating and OCD pathophysiology. The goal of this study was to examine the relationships between sensorimotor gating, compulsive behavior, and striatal dopamine receptor levels in Sapap3 knockout mice (KOs), a widely used preclinical model system for OCD research. We found a trend for disruption of sensorimotor gating in Sapap3-KOs using the translational measure prepulse inhibition (PPI); however, there was significant heterogeneity in both PPI and compulsive grooming in KOs. Disruption of PPI was significantly correlated with a more severe compulsive phenotype. In addition, PPI disruption and compulsive grooming severity were associated with reduced dopamine D1 and D2/3 receptor density in the nucleus accumbens core (NAcC). Compulsive grooming progressively worsened in Sapap3-KOs tested longitudinally, but PPI disruption was first detected in high-grooming KOs at 7 months of age. Through detailed characterization of individual differences in OCD-relevant behavioral and neurochemical measures, our findings suggest that NAcC dopamine receptor changes may be involved in disruption of sensorimotor gating and compulsive behavior relevant to OCD. Intrusive thoughts (obsessions) and uncontrollable actions (compulsions) are the core clinical features of OCD. Subjects with OCD also show disturbances in sensorimotor gating8, a filtering process that impacts the content and organization of what is consciously perceived by an individual. It has been proposed that sensorimotor gating deficits in OCD may facilitate intrusive thoughts and impair inhibitory control over compulsive actions, although these relationships have not been clearly demonstrated in patients.Obsessive compulsive disorder (OCD) is a severe neuropsychiatric disorder affecting 1–3% of the population10 or site specific manipulations in dorsal or ventral striatum13. Dopamine system disturbances have also been described in the striatum in patients with OCD18 using in vivo molecular imaging with single photon emission computerized tomography (SPECT) and positron emission tomography (PET). Binding of striatal dopamine D1 and D2/3 receptors is reduced in OCD patients19, and dopamine transporter binding is increased20. It has been proposed that these alterations may represent compensatory changes in response to elevated dopamine tone, consistent with evidence that transdiagnostic compulsive behaviors are associated with elevated striatal dopamine. Specifically, increased cue-evoked striatal dopamine release has been observed via PET imaging in cocaine users, subjects with binge eating disorder, and patients with Parkinson’s disease who develop compulsive behavior following dopamine agonist treatment24. There is also evidence that drugs that increase dopamine signalling can exacerbate compulsive behavior in OCD patients25. Further supporting the role of elevated dopamine in the manifestation of OCD symptoms, dopamine antagonists can be useful as an adjunct therapy in OCD patients that don’t show clinical improvement following treatment with first-line selective serotonin reuptake inhibitors (SSRIs)26. Together, these results suggest a potential relationship between alterations in striatal dopamine signalling and disruption of both sensorimotor gating and compulsive behavior in OCD.Underlying mechanisms responsible for disruption of sensorimotor gating in OCD are unclear; however, disturbances in striatal dopamine have been implicated in both the regulation of sensorimotor gating and manifestation of compulsive behavior. In rodent models sensorimotor gating is disrupted by increased dopamine neurotransmission following systemic administration of dopamine agonists/releasers27. For example, studies in mouse models suggest that elevated striatal dopamine and disruption of dorsal striatum function may have relevance to disruption of PPI in Tourette Syndrome29. Although prior studies have demonstrated PPI deficits in pharmacologic models of relevance to OCD31, sensorimotor gating deficits and their relationship to compulsive behaviors have not been characterized in transgenic mouse models. Here, we examined PPI in Sapap3 knockout mice (KOs), a widely used model system for OCD research34 that displays compulsive grooming, anxiety32, and cognitive changes in tasks examining reversal learning36 and habit learning38. Sapap3-KOs also show hyperactivity in the dorsal and central striatum (CS)39 that would be predicted to influence PPI; in contrast, the ventral striatum has not been thoroughly characterized in this model system40. The goal of this study was therefore to probe the relationship between PPI, striatal dopamine receptor levels, and compulsive behavior in Sapap3-KOs using behavioral testing and ex vivo autoradiography.Preclinical model systems can be used to gain mechanistic insight into the relationship between dopamine signalling, impaired sensorimotor gating, and other OCD-relevant behaviors using a straightforward translational paradigm: prepulse inhibition (PPI) of the acoustic startle response27.28 = 1.70), with both groups showing similar increased PPI with higher prepulse intensities  = 87.4, p < 0.0001). However, visual inspection of the data and an F test to compare variance between the groups demonstrated more variability in KOs compared to WTs  = 3.3, p = 0.0499), prompting us to determine whether this heterogeneity within KOs mapped onto other behavioral measures. As expected, Sapap3-KOs groomed significantly more than WTs  control mice at ~ 8 months of age, when approximately half of KOs 10/18) showed lesions resulting from compulsive grooming. Analysis of average %PPI revealed a trend for differences between genotypes  = 8.5, p = 0.0013). Further examination of this heterogeneity using unbiased k-means clustering of grooming and PPI data showed that KO mice could be grouped into three clusters that largely corresponded with lesion status  = 4.6, p = 0.042), and there was a trend for interaction with striatal region of interest suggesting that this effect may be more prominent in NAcC . Reduced D2/3 density in KOs was also associated with individual differences in compulsive grooming and disruption of PPI. Again this effect was selective to NAcC, with reduction of D2/3 binding associated with both disruption of PPI  of animals described in Fig. D1 receptor density was not significantly different between genotypes  = 4.8; p = 0.037). There was a trend for genotype x striatal subregion interaction (p = 0.094), suggesting that this effect may be more prominent in CS. In contrast to striatal dopamine receptor densities, DAT binding density in NAcC and CS was not correlated with changes in PPI or grooming in Sapap3-KOs  using ex vivo autoradiography  = 15.8, p < 0.0001, trajectories of individual animals are shown in Figure 39); however, this small effect-size difference was not detectable during the less frequent (monthly) testing performed in the current study.It is hypothesized that impaired sensorimotor gating in OCD may contribute to disruption of inhibitory control over compulsive actions. To test whether disruption of PPI in Sapap3-KOs might precede development of the compulsive grooming phenotype, and thereby contribute to the onset of compulsive behavior, PPI and grooming were both assessed monthly from 2 months (before the development of lesions) until 8 months of age  in male and female Sapap3-KOs and WT littermates. Time spent grooming progressively increased with age  = 29.2, p < 0.0001). However, analysis of startle amplitude revealed age-dependent genotype differences  = 3.8, p = 0.001). Whereas startle amplitude decreased in WT mice as they aged (consistent with other studies in mice42), KOs had relatively stable startle amplitude over time. Since group differences in startle amplitude confound interpretation of PPI, we therefore focused analysis on 6–8 months of age when startle amplitude did not differ between the groups  = 0.7, p = 0.49); however, KO-L showed reduced PPI relative to the other two groups at 7 and 8 months  = 9.2, p = 0.0005; 8 months: F = 7.8, p = 0.0013). PPI was significantly correlated with grooming at 8 months of age , but not at 6–7 months of age , there was a trend towards reduced PPI in KOs  present across the diagnosis of OCD, similar to our current examination of PPI in Sapap3-KOs displaying a range of severity of compulsive behavior.The observed association between severity of compulsive grooming and disruption of PPI in the Sapap3-KO model could reflect that one of these behaviors plays a causal role in the presentation of the other, or that a common neural mechanism(s) contributes to the development or manifestation of both behaviors. Our findings suggest that if a causal relationship is present, compulsive behavior influences disruption of PPI, and not the other way around. This conclusion is based on earlier onset of the severe grooming phenotype, as well as observation of PPI impairment in only a subset of high-grooming mice. A clear relationship between PPI and other OCD symptoms has not been established in previous clinical studies. Early studies in medicated patients demonstrated that severity of PPI impairment was significantly associated with severity of OCD symptoms as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS)36, and these findings have been replicated by other laboratories43. Others have also recently demonstrated aberrant habit learning in Sapap3-KOs, and have begun to examine potential relationships between compulsive grooming and flexible cognition in this context38. In the first study, increased habitual behavior in Sapap3-KOs  was not directly compared to compulsive grooming38. However, mice were 7–12 weeks old at the start of habit training, suggesting that a severe compulsive grooming phenotype was not present based on the results of our study. In the second study, which used different testing conditions that specifically promoted habitual behavior in WT mice, Sapap3-KOs showed more goal-directed behavior . Although analysis of the relationship between habitual behavior and compulsive grooming was underpowered, there was a trend for a bias towards habitual behavior in low grooming Sapap3-KOs and flexible goal-directed behavior in high grooming Sapap3-KOs37. These studies of cognitive flexibility largely support the idea that OCD-relevant cognitive changes and compulsive grooming are distinct behavioral domains in Sapap3-KOs, whereas our current findings suggest that compulsive grooming and disruption of PPI in Sapap3-KOs may be related. The Sapap3-KO model therefore serves as a useful system for further dissection of the contributions of overlapping versus distinct circuits associated with different OCD-relevant behavioral domains. This is an important question given that distinct patterns of activity in striatum and prefrontal cortex are associated with symptoms vs cognitive deficits44. Better understanding of these behavior-specific neural changes may thus be valuable for guiding the development of more effective treatments.Interestingly, we recently demonstrated that disruption of cognitive task is not associated with severity of compulsive grooming in Sapap3-KOs19. Compulsive behavior and disruption of PPI are both typically associated with a hyperdopaminergic state in striatum45. Given this, it is plausible that the observed correlations in Sapap3-KOs between severity of these OCD-relevant phenotypes and reduced dopamine receptor density may reflect compensatory downregulation of receptors in response to increased dopamine tone. This has been proposed as a likely mechanism for decreased striatal dopamine receptor binding observed using PET imaging in OCD patients16, and is supported by our observation of increased DAT binding density in Sapap3-KOs which may reflect increased dopaminergic innervation/release . However, we cannot rule out negative consequences of this early change in grooming that we have not measured . Importantly, this behavioral change in early adulthood may provide insight regarding neural mechanisms early in pathophysiological development that could be targeted by preventive interventions.To our knowledge, these studies are the first to thoroughly investigate the longitudinal progressive development of the compulsive grooming phenotype in Sapap3-KOs, and raise the important question of whether there are distinct neural changes that lead to low vs high grooming KOs. Recently it has been reported that Sapap3-KO mice do not show age-dependent changes in grooming phenotype in a study using a cross-sectional design in a group of ~ 2–5 month old Sapap3-KO miceGiven the significant heterogeneity in compulsive grooming severity in Sapap3-KOs, observed both within animals (across time) and between animals at a given age, it will be important to report grooming severity in future research detailing the molecular, cellular, and circuit disturbances present in this model. Careful examination of these individual differences may help to understand neural mechanisms associated with resilience vs susceptibility to the development of compulsive behavior. Although this is outside the scope of the current studies, earlier stage and longitudinal measurements of neural changes  associated with the emergence of the compulsive grooming phenotype will provide important insight about underlying pathophysiological mechanisms.Sapap3 variants play a role in OCD48, Sapap3 is not a leading candidate for OCD genetic risk (though note that current genome wide association studies in OCD are underpowered49). However, our lab recently demonstrated decreased Sapap3 gene expression in orbitofrontal cortex and striatum in post mortem tissue from human subjects with OCD, supporting a potential role for Sapap3 in OCD pathophysiology50. In further support of its use for OCD research, the Sapap3-KO mouse has abnormalities in OCD-relevant behavioral constructs , and exhibits therapeutic response to treatments that can be effective in OCD patients including repeated fluoxetine administration and deep brain stimulation51. Nonetheless, further examination of the relationship between striatal dopamine measures, compulsive behavior, and sensorimotor gating is warranted in other OCD-relevant model systems and human subjects with OCD to better understand the relevance of our findings to OCD pathophysiology. Another limitation is that these studies rely on correlative evidence to link striatal dopamine receptor changes with severity of OCD-relevant behaviors. We propose that our observations provide indirect evidence that increased striatal dopamine may be a common mechanism for generation of distinct OCD-relevant behaviors. We believe these findings warrant further causal mechanistic examination of dopaminergic regulation of behavioral disturbances relevant to OCD, which is beyond the scope of the current studies.There are several limitations of these studies that will be important to address in future research. First, although there is some evidence that rare These studies are the first to demonstrate an association between the development of OCD-relevant compulsive grooming and disruption of PPI in a transgenic mouse model. Through ex vivo neurochemical analysis of brain tissue from mice that have undergone behavioral testing, we have identified a potential role of reduced NAcC dopamine receptor density in the manifestation of these maladaptive behaviors. By leveraging heterogeneity in the penetrance and progression of OCD-relevant behaviors in this preclinical model system, we have highlighted associations that may be relevant to neural changes occurring in distinct subsets of patients with OCD and related disorders.32. Mice were housed in groups of 2–5 same-sex mice in individually ventilated cages, with ad libitum access to standard chow and drinking water, in 12:12 light/dark cycle. All behavioral testing was conducted in the light cycle. All experimental procedures were approved by the Institutional Animal Care and Use Committee at the University of Pittsburgh, and all methods were carried out in compliance with National Institutes of Health (NIH) guidelines for the care and use of laboratory animals. This study was also carried out in compliance with the ARRIVE guidelines.Male and female Sapap3-KO and WT littermates were bred from heterozygous x heterozygous breeding pairs on a C57/BL6 background, and were derived from a colony initially established at MIT by Dr Guoping Feng52, to examine the effects of three prepulse intensities  on the magnitude of acoustic startle reflex elicited by 120 dB pulse of noise. All mice were tested in “startle only” session  prior to first PPI session for habituation to testing procedures. Following standard protocols, startle blocks 2 and 3 were used to calculate PPI, and startle blocks 2/3 were compared to startle blocks 1 and 4 to assess startle habituation27. PPI is calculated as follows:PPI was tested using SR-LAB startle response system  with methods similar to those previously describedBecause these studies examined mice at an age where poor hearing could potentially impact PPI, mice were excluded from analysis if they exhibited very weak startle response to pulse alone trials relative to measurements made in the absence of a startling pulse  for 2 consecutive days (20 min/session). Mice were then videotaped for a 20 min session, and grooming was manually scored offline by trained experimenters blind to genotype and PPI values. Grooming time is calculated as the sum of time spent grooming the face, grooming the body, and scratching.A trained experimenter blind to genotype and mouse behavioral scores rated each animal for evidence of skin lesions on the day of PPI testing. Mice that had regions on the face or body where skin was raw, inflamed, or bloody were classified in the “lesion” group. In line with institutional IACUC protocols, mice classified with lesions were treated using topical antibiotic as needed , with the exclusion of the day of and prior to behavioral testing.54. Mice were sacrificed by cervical dislocation followed by rapid decapitation. Brains were then extracted, frozen immediately on dry ice, and stored at − 80 °C. 20 μm sections were cut on a cryostat  and stored on slides  at − 80 °C until autoradiography experiments were performed.Fresh frozen brains were obtained from mice assessed in PPI and grooming tests, and processed according to standard protocols to detect dopamine D1 and D2/3 receptor and DAT binding using specific radioligands3H]-SCH-23390 for D1 binding (2 nM), [3H]-Raclopride for D2/3 binding (5 nM), [3H]-GBR-12935 for DAT binding (2 nM) . To terminate radioligand incubation, slides were dipped and then washed in ice cold buffer . Following washes slides were dipped in ice cold dH2O and allowed to completely airdry before they were opposed to BioMax MR film  with 3H standards . More details regarding reagents and conditions used for specific autoradiography experiments are included in Table 54. MR films were developed using MINI-MED 90 X ray film development system . Developed films were then scanned at 2400dpi  and luminosity was measured using Photoshop  bilaterally in each region of interest on TB and NSB slides. These values were converted to radioactivity (uCi/g) using a standard curve, and average NSB radioactivity was subtracted from average TB to give specific binding (SB) used for analysis. Figure Slides for total binding (TB) included tissue from 2 animals from different experimental groups, with 4 striatal sections collected every 200 μm. Slides for non-specific binding (NSB) included tissue from 4 animals with 2 sections collected every 400 μm. Position of subjects on the slides was counter-balanced across groups to account for fluid distribution during radioisotope incubation, and all slides for a given assay were incubated on the same day with the same binding solutions. Slides were thawed for 1 h before preincubation in buffer . Following preincubation, slides were allowed to completely airdry for > 1 h before incubation in radioligand solutions. The following radioisotopes were used: . Analysis of behavioral data separated by sex demonstrated no evidence for sex differences Figure . Sexes w39, and is reproduced with permission , 17 KO ] were acclimatized twice to grooming chambers between postnatal day (PND) 18–20. Mice were weaned at PND21, tested the following day, and then tested weekly until week 8. Data for week 8 of this experiment has been published elsewheren Figure .Welch’s t-tests were used for analyses of data where the groups had unequal variance (e.g. PPI when KOs were analysed as one heterogeneous group, Fig. Supplementary Information


Objective: The relation between cognition and hearing loss has been increasingly paid high attention, however, few studies have focused on the role of high-frequency hearing loss in cognitive decline. This study is oriented to role of hearing loss especially high-frequency hearing loss in cognitive impairment among elderly people (age ≥ 60 years).Methods: The Montreal Cognitive Assessment Scale (MoCA) and pure tone audiometry were used to investigate the hearing loss and cognitive function of 201 elderly people older than 60 years. Factors possibly related to cognitive impairment including age, years of education, occupation, living conditions, history of otologic diseases, and high blood pressure were registered. This study consisted of two parts. First, univariate analysis and multiple linear regressions were performed to analyze the possible influencing factors of cognitive function among the 201 elderly people. Second, average hearing thresholds of low frequencies , intermediate frequencies , and high frequencies  were calculated to screen out 40 cases with high-frequency hearing loss alone and 18 cases with normal hearing. Univariate analysis was used to compare the general condition, cognitive function, and each cognitive domain between the two groups, analyzing the relation between high-frequency hearing loss and cognitive function.Result: We found that age, years of education, pure tone average (PTA), occupation, living condition, history of otologic diseases, years of self-reported hearing loss, and hypertension history were related to cognitive function. Furthermore, age, education experience, duration of self-reported hearing loss, and hypertension were independent factors (p < 0.05). PTA was negatively related with attention, orientation, and general cognition (p < 0.05). There were only 18 cases (9.0%) with normal hearing, and 40 cases (19.9%) with abnormal high-frequency hearing alone. The overall cognitive function showed no significant difference between them (p > 0.05); in contrast, the speech and abstract ability were significantly decreased in cases with high-frequency hearing loss (p < 0.05).Conclusion: The increase of PTA among the elderly may affect the overall cognition by reducing attention and orientation. High-frequency hearing loss alone can affect the language and abstract ability to a certain extent, which is worthy of more attention. Lancet at the 2017 Alzheimer’s Association International Conference in London  senn London ; (3) infn London ; and (4)n London .However, most previous studies have focused on the correlation between speech-frequency hearing loss and cognitive function, while ignoring the importance of high-frequency hearing loss. Studies have shown that the incidence of high-frequency hearing loss is significantly higher than that of speech frequency (REF). Among people aged 20 to 29 years, the proportion of combined speech-frequency hearing loss is only 2.2%, whereas the proportion of high-frequency hearing loss can be as high as 7% . And thiA total of 201 elderly volunteers were enrolled in this study from the free clinic of 2019 Ear Day at Peking University People’s Hospital. The detailed inclusion criteria were as follows: (1) age ≥ 60 years, (2) sensorineural hearing loss, and no significant difference in hearing threshold between two ears, (3) no history of otitis media, sudden deafness history, and acoustic neuroma, and (4) no mental illness history and could cooperate with the whole study process. All study subjects underwent pure tone audiometry test, otoscope examination, and cognitive function assessment. The basic information including sex, age, living condition, years of education, occupation, self-reported hearing loss, tinnitus, ear diseases history, and some chronic disease history  was collected by face-to-face survey with questionnaires. All included subjects and (or) their family members were asked to fill the questionnaire under the supervision of the same experienced physician.A questionnaire on cognitive function and influencing factors was designed according to previous study . All theThe cognitive function assessments of all participants were completed with a unified Montreal Cognitive Assessment Scale (MoCA) questionnaire survey, which was administered to assess the global cognitive level by the same neurologist. The MoCA scale consisted of eight several subtasks to assess different cognitive domains, of which the immediate memory subdomain is not scored. The other seven cognitive domains and corresponding scores were visuospatial and executive function for 5 points, language ability for 3 points, attention for 6 points, orientation for 6 points, delayed memory for 5 points, naming for 3 points, and abstract ability for 2 points . MoreoveThe pure tone audiometry and the otoscope examination were all completed in the ENT departments of Peking University People’s Hospital. According to the World Health Organization criteria (1997), the average value of 500−, 1, 000−, 2, 000−, and 4,000-Hz air conduction pure tone average (PTA) hearing thresholds was used for defining the hearing loss degree, including normal hearing (≤25 dB), mild (26–40 dB), moderate (41–60 dB), severe (61–80 dB), and profound hearing loss (>80 dB). On the other hand, the average hearing thresholds of low frequencies , intermediate frequencies , and high frequencies  were all calculated separately to select a group of subjects with hearing loss at only high frequencies  (HHL group). Except for average hearing threshold of 4 and 8 k is greater than 25 dB, the hearing thresholds of other frequencies  of patients in the HHL group are all not higher than 25 dB (HHL group).The Peking University People’s Hospital Ethical permission committee approved study (2019PHB084-01), and all subjects provided their informed consents.p < 0.05.Statistical analyses in this study were performed with SPSS 24.0 software package . This study consisted of two parts. First, univariate analysis and multiple linear regressions were performed to analyze the possible influencing factors of cognitive function among the 201 elderly people. Second, average hearing thresholds of low frequencies , intermediate frequencies , and high frequencies  were calculated to screen out 40 cases with high-frequency hearing loss alone (HHL) and 18 cases with absolutely normal hearing (NH). Univariate analysis was used to compare the general condition, cognitive function, and each cognitive domain between the two groups, analyzing the relation between high-frequency hearing loss and cognitive function. All the statistical significances were at the level There were 201 participants . The overall average age was 72.06 ± 5.90 years, with a range of 60 to 90 years. According to PTA values, the number of participants with normal hearing, mild, moderate, severe, and profound hearing loss were 39 (19.4%), 65 (32.3%), 80 (39.8%), 17 (8.5%), and 0 (0%), respectively. The overall average score of MoCA scale assessment was 24.64 ± 3.68, with a range of 11 to 30.p < 0.05). The above factors were all included in a multivariate analysis, which indicated that age, years of education, years of self-reported hearing loss, and hypertension were independent factors related to cognitive function (p < 0.05). The elderly with older age, shorter years of education, longer time of self-conscious hearing loss, and high blood pressure were more likely to be associated with cognitive dysfunction.As shown in p < 0.05). No other cognitive domains showed significant differences between these groups (p > 0.05)  .p = 0.013 vs. p < 0.001). Meanwhile, no other basic information we studied showed significant differences between these two groups (p > 0.05). As shown in p = 0.027 vs. p = 0.005). Meanwhile, no significant differences were found in other cognitive domains and overall cognitive function (p > 0.05).There were only 18 subjects (9.0%) with completely normal hearing levels <25 dB) at all frequencies tested, including 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, and 8.0 kHz . On the other hand, the number of subjects with hearing loss (>25 dB) at only high frequencies (4.0 k and 8.0 kHz) was 40 (19.9%) . As shown in 5 dB at aAs the aging problem increasing worldwide, hearing loss as one of the most common problems among the elderly has drawn more and more attention. Studies have shown that hearing loss is a modifiable age-associated condition linked to dementia ; howeverThe results of this study indicated that among the elderly, occupation, living conditions, ear diseases history, and PTA were the influencing but not independent influencing factors of cognitive function, whereas age, educational experience, years of self-reported hearing loss, and whether accompanied by hypertension were independent related factors of cognitive function. Among them, age is unchangeable, hypertension can be regulated by tertiary prevention, the years of education requires the joint efforts of the whole society, whereas the years of self-reported hearing loss is the only factor that can be changed by early hearing interventions.As early as 2001, a clinical study conducted by However, there are several researchers who believe that the association between hearing loss and cognitive impairment is caused by overestimation, namely, overdiagnosis hypothesis, in which degraded hearing, rather than cognitive function, impacts performance on certain neuropsychological tests. First, despite that hearing loss usually occurs earlier than dementia or cognitive impairment, suggesting hearing loss may lead to dementia or cognitive impairment, it may also be due to the fact that patients with hearing loss usually receive more neuropsychological tests. Therefore, it is easier to diagnose the accompanying cognitive impairment . Or moreIn this study, we found that hearing loss has significantly related to the cognitive decline, which is consistent with the previous study conducted by In addition, our results suggested that the PTA has a significant correlation with orientation and abstract ability, indicating that hearing loss might affect the cognitive function by affecting orientation and abstract ability. Orientation is the ability of the individual to perceive signal and recognize the surrounding environment  and one’s own state . Hearing loss causes the decline of hearing sensitivity and the speech perception in noise , consequPresbycusis, the hearing of the old man, has been recognized since the late 19th century , and theThe results of this study showed that pure high-frequency hearing loss has no obvious correlation with the general cognitive function, but was significantly related with the abstract and speech function; that is, early high-frequency hearing loss will affect the speech and abstract ability among the elderly. Some studies have already shown that the high-frequency sensitivity has a significant correlation with speech recognition ability, especially speech perception in noise ,which isOf course, this study also has some limitations. First, the 201 elderly volunteers were enrolled from the free clinic of 2019 Ear Day at Peking University People’s Hospital, which would cause selection bias, resulting in the higher proportion of hearing loss in this study. Second, the sample size of this study is relatively small, only 40 cases of pure high-frequency hearing loss, and 18 cases of normal hearing. Finally, in this study, we chose only a general cognitive assessment scale, the MoCA scale, for ease of operation and separate scales for each cognitive domain, and cognitive behavioral tests will be added in subsequent studies.Age, hypertension, years of self-reported hearing loss, and years of education are independent related factors for cognitive decline among the elderly. PTA was not an independent influencing factor of cognitive function, which may affect cognitive function by influencing orientation and abstract ability. Pure high-frequency hearing loss may affect the speech and abstract ability of elderly patients, but not significantly affect their global cognitive function. The early high-frequency hearing loss is not easy to be detected by the elderly, as it is relatively mild and does not significantly affect the cognitive ability. But as the result of this study, it may have a certain impact on the speech and abstract ability, which is necessary to be detected and prevented early.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.TD, XM, JZ, MD, and LY contributed to the study conception and design. TD, XM, and JZ supervised this research and wrote the first draft of the manuscript. All authors contributed to the material preparation, data collection, and read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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