Clarin-2 gene supplementation durably preserves hearing in a model of progressive hearing loss.

Hearing loss is a major health concern affecting millions of people worldwide with currently limited treatment options. In clarin-2-deficient Clrn2-/- mice, used here as a model of progressive hearing loss, we report synaptic auditory abnormalities in addition to the previously demonstrated defects of hair bundle structure and mechanoelectrical transduction. We sought an in-depth evaluation of viral-mediated gene delivery as a therapy for these hearing-impaired mice. Supplementation with either the murine Clrn2 or human CLRN2 genes preserved normal hearing in treated Clrn2-/- mice. Conversely, mutated forms of CLRN2, identified in patients with post-lingual moderate to severe hearing loss, failed to prevent hearing loss. The ectopic expression of clarin-2 successfully prevented the loss of stereocilia, maintained normal mechanoelectrical transduction, preserved inner hair cell synaptic function, and ensured near-normal hearing thresholds over time. Maximal hearing preservation was observed when Clrn2 was delivered prior to the loss of transducing stereocilia. Our findings demonstrate that gene therapy is effective for the treatment of post-lingual hearing impairment and age-related deafness associated with CLRN2 patient mutations.

Tinnitus and distress: an electroencephalography classification study.

There exist no objective markers for tinnitus or tinnitus disorders, which complicates diagnosis and treatments. The combination of EEG with sophisticated classification procedures may reveal biomarkers that can identify tinnitus and accurately differentiate different levels of distress experienced by patients. EEG recordings were obtained from 129 tinnitus patients and 142 healthy controls. Linear support vector machines were used to develop two classifiers: the first differentiated tinnitus patients from controls, while the second differentiated tinnitus patients with low and high distress levels. The classifier for healthy controls and tinnitus patients performed with an average accuracy of 96 and 94% for the training and test sets, respectively. For the distress classifier, these average accuracies were 89 and 84%. Minimal overlap was observed between the features of the two classifiers. EEG-derived features made it possible to accurately differentiate healthy controls and tinnitus patients as well as low and high distress tinnitus patients. The minimal overlap between the features of the two classifiers indicates that the source of distress in tinnitus, which could also be involved in distress related to other conditions, stems from different neuronal mechanisms compared to those causing the tinnitus pathology itself.

Is CMV PCR of inner ear fluid during cochlear implantation a way to diagnose CMV-related hearing loss?

To evaluate the diagnostic performance of cytomegalovirus (CMV) polymerase chain reaction (PCR) on inner ear fluid collected during cochlear implantation and to assess its interest in current practice. This monocentric prospective study included consecutive children presenting with severe to profound sensorineural hearing loss (SNHL) who were candidates for unilateral and/or bilateral cochlear implantation. The etiology of the SNHL was determined before cochlear implantation when possible. During the surgery, drop-like samples of inner ear fluid and blood were collected. CMV PCR was then performed on both samples. Between January 2017 and September 2021, 113 children with severe to profound SNHL underwent cochlear implantation with inner ear fluid collection. Among these children, 77 of them presented with a known cause of SNHL (68%) and 36 of them had an unknown cause of SNHL at the time of surgery (32%). Sensitivity and specificity of the CMV PCR on inner ear fluid were 60% (95% CI: [49-71]) and 98% (95% CI: [96-100]), respectively. Positive and negative predictive values were 90% (95% CI: [83-97]) and 92% (95% CI: [86-98]), respectively. A sensitivity analysis according to age at cochlear implantation showed a decrease with age. CONCLUSION: Sampling of inner ear fluid during cochlear implant surgery is an interesting, simple and safe way to diagnose CMV-related hearing loss, especially when the diagnosis of congenital infection can no longer be confirmed. However, the sensitivity decreases with age. TRIAL REGISTRATION: NCT04724265 What is Known: • Congenital cytomegalovirus infection is the leading infectious cause of neurological disabilities and sensorineural hearing loss in children. In the absence of systematic screening at birth, many cCMV infections go undetected and are often undiagnosed despite the development of sensorineural sequelae.  • Nearly 40% of indications for cochlear implantation are of unknown etiology. WHAT IS NEW: • Performing CMV PCR on inner ear fluid at the time of cochlear implantation is a safe way with high diagnostic performance (PPV = 90%, NPV = 92%) to detect a CMV-related hearing loss. • This sample may be interesting in cases of unknown cause of hearing loss in order to identify undiagnosed cCMV infections.

Links Between Swallowing and Consciousness: A Narrative Review.

This literature review explores a wide range of themes addressing the links between swallowing and consciousness. Signs of consciousness are historically based on the principle of differentiating reflexive from volitional behaviors. We show that the sequencing of the components of swallowing falls on a continuum of voluntary to reflex behaviors and we describe several types of volitional and non-volitional swallowing tasks. The frequency, speed of initiation of the swallowing reflex, efficacy of the pharyngeal phase of swallowing and coordination between respiration and swallowing are influenced by the level of consciousness during non-pathological modifications of consciousness such as sleep and general anesthesia. In patients with severe brain injury, the level of consciousness is associated with several components related to swallowing, such as the possibility of extubation, risk of pneumonia, type of feeding or components directly related to swallowing such as oral or pharyngeal abnormalities. Based on our theoretical and empirical analysis, the efficacy of the oral phase and the ability to receive exclusive oral feeding seem to be the most robust signs of consciousness related to swallowing in patients with disorders of consciousness. Components of the pharyngeal phase (in terms of abilities of saliva management) and evoked cough may be influenced by consciousness, but further studies are necessary to determine if they constitute signs of consciousness as such or only cortically mediated behaviors. This review also highlights the critical lack of tools and techniques to assess and treat dysphagia in patients with disorders of consciousness.

Audiovestibular Consequences of Congenital Cytomegalovirus Infection: Greater Vulnerability of the Vestibular Part of the Inner Ear.

OBJECTIVES: To investigate the impact of congenital cytomegalovirus infection on cochlear and vestibular function. DESIGN: This retrospective study conducted between March 2014 and March 2020 included children with confirmed congenital cytomegalovirus infection who underwent a complete audio-vestibular evaluation. It included a bithermal caloric test, a video head impulse test and a cervical vestibular evoked myogenic potential associated with a complete hearing assessment. RESULTS: The cohort of 130 children included in the study had a median age of 21 months (interquartile range: 12 to 37 months). Eighty-three children (64%) showed an inner ear impairment (both cochlear and vestibular). The vestibular part of the inner ear was significantly more frequently impaired than the cochlear part (ρ = 0.003). Sixty-two children (48%) showed confirmed hearing impairment. The severity of hearing loss was variable, with a high proportion of profound hearing loss (30/62, 48%), which was often bilateral (47/62, 76%). The vestibular assessment showed a canal function disorder in 67 children (88%) and an otolith function disorder in 63 children (83%; ρ = 0.36). The video head impulse test was significantly less altered (64%) compared with the bithermal caloric test (80%; ρ = 0.02) and the cervical vestibular evoked myogenic potential (83%; ρ = 0.009). Only seven out of 83 children (8%) showed hearing loss without vestibular dysfunction, of which only one had a normal hearing screening test at birth. For the children who passed the hearing screening test at birth and presented an inner ear impairment [n = 36, median age: 16 (11 to 34) months], vestibular disorders were later found in 35 children (97%) and 17 of them (47%) developed hearing loss secondarily. This underlines the importance of assessing both vestibular and auditory parts of the inner ear. When comparing the agreement of cochlear and vestibular impairment, the severity and the laterality of the impairment were low [Cohen's kappa 0.31 (0.22 to 0.40) and 0.43 (0.32 to 0.55), respectively]. CONCLUSION: In our study, we demonstrated that although both cochlear and vestibular parts of the inner ear can be impaired by congenital cytomegalovirus infection, the vestibular part seems more often impaired compared with the cochlear part. This underlines the importance of vestibular evaluation in the follow-up of cytomegalovirus-infected children associated with hearing assessment.

Predictors of cochleovestibular dysfunction in children with congenital cytomegalovirus infection.

The purpose of this study is to assess the predictive factors of both hearing and vestibular impairment in congenitally cytomegalovirus-infected children (cCMV) through a multivariate analysis of clinical and imaging characteristics collected during pregnancy and at birth. This retrospective study was conducted between March 2014 and March 2020, including confirmed congenitally CMV-infected children with a complete vestibular and hearing assessment. Data concerning pregnancy, date of infection, clinical characteristics, and symptomatology at birth were collected. In total, 130 children were included, with a median age of 21 months. Eighty-three children (64%) presented with an inner ear impairment (both cochlear and vestibular impairment). Sex, modality of maternal infection (seroconversion or reactivation), pregnancy term, weight and head circumference at birth, neonatal clinical signs of infection, and treatment were not significantly correlated with inner ear impairment. However, multivariate analysis confirmed that there are two independent predictive factors of inner ear impairment: antenatal imaging lesions (ORa = 8.02 [1.74; 60.27], p-value = 0.01) and infection during the first trimester (ORa = 4.47 [1.21; 19.22], p-value = 0.03). Conversely, infections occurring during the second trimester were rarely associated with inner ear impairment: 4/13 (31%) in our series, with vestibular impairment alone (4/4) and no hearing loss. None of the children infected during the third trimester developed inner ear dysfunction. CONCLUSION: Besides the symptomatic status of the CMV infection at birth, we found that antenatal imaging brain damage and early infection (mainly during the first trimester) constitute the two best independent predictive factors of inner ear involvement in congenitally CMV-infected children. WHAT IS KNOWN: • Congenital cytomegalovirus infection is the leading infectious cause of neurological disabilities and sensorineural hearing loss in children and responsible of vestibular disorders, which are probably underestimated. • No articles have yet defined the predictive factors of the entire inner ear impairment (vestibule and cochlea). WHAT IS NEW: • The timing of the infection during pregnancy (first and second trimester, ORa=4.47) and antenatal imaging lesions (ORa=8.02) are independently predictive (in a multivariate analysis) of inner ear involvement. • The symptomatic status at birth is a poor predictor of inner ear impairment.

Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions.

The inner ear is responsible for both hearing and balance. These functions are dependent on the correct functioning of mechanosensitive hair cells, which convert sound- and motion-induced stimuli into electrical signals conveyed to the brain. During evolution of the inner ear, the major changes occurred in the hearing organ, whereas the structure of the vestibular organs remained constant in all vertebrates over the same period. Vestibular deficits are highly prevalent in humans, due to multiple intersecting causes: genetics, environmental factors, ototoxic drugs, infections and aging. Studies of deafness genes associated with balance deficits and their corresponding animal models have shed light on the development and function of these two sensory systems. Bilateral vestibular deficits often impair individual postural control, gaze stabilization, locomotion and spatial orientation. The resulting dizziness, vertigo, and/or falls (frequent in elderly populations) greatly affect patient quality of life. In the absence of treatment, prosthetic devices, such as vestibular implants, providing information about the direction, amplitude and velocity of body movements, are being developed and have given promising results in animal models and humans. Novel methods and techniques have led to major progress in gene therapies targeting the inner ear (gene supplementation and gene editing), 3D inner ear organoids and reprograming protocols for generating hair cell-like cells. These rapid advances in multiscale approaches covering basic research, clinical diagnostics and therapies are fostering interdisciplinary research to develop personalized treatments for vestibular disorders.

Olfactory function in congenital cytomegalovirus infection: a prospective study.

Congenital cytomegalovirus (CMV) infection leads to olfactory bulb lesions in the fetus, yet little is known about its impact on olfaction after birth. Here, we have assessed in a prospective study conducted on children in two French hospitals from 2016 to 2019, infection severity and olfactory performance after congenital CMV infection. Children with congenital CMV infection aged 3 to 10 years and healthy controls (CTL) matched for age and sex to CMV children symptomatic at birth (sCMV) were enrolled. Olfactory discrimination was assessed using mono-odorants and binary mixtures. Data were analyzed for 54 children with PCR-confirmed congenital CMV infection, including 34 sCMV (median [IQR] age, 6 [5-8] years; 19 [55.9%] male), and 20 CMV asymptomatic at birth (aCMV, median [IQR] age, 4 [3-6] years; 12 [60.0%] male). sCMV were compared to 34 CTL children. Olfactory scores in CMV-infected children were independent from vestibular deficit and hearing loss. The olfactory score was efficient to discriminate between CTL and sCMV for children > 6 years (area under the receiver-operating characteristic curve (AUC, 0.85; P = 0.0006), but not for children < 7 years. For children > 6 years, the proportion of children with total olfactory score < 4 differed between sCMV and CTL groups (91.2% and 18.7%, P < 0.001), but not between aCMV and age-matched healthy control groups.   Conclusion: Congenital CMV infection is associated with reduced olfactory performance in children with infection symptoms at birth.   Clinical trial registration: NCT02782988 (registration date: May 26, 2016). What is Known: •Congenital cytomegalovirus infection leads to olfactory bulb lesions in the fetus, yet little is known about its impact on olfaction after birth. •Depending on neonatal clinical presentation, children are either categorized as having a symptomatic or asymptomatic infection at birth. What is New: •Congenital cytomegalovirus infection is associated with reduced olfactory performance in children with infection symptoms at birth.

Swallowing in individuals with disorders of consciousness: A cohort study.

BACKGROUND: After a period of coma, a proportion of individuals with severe brain injury remain in an altered state of consciousness before regaining partial or complete recovery. Individuals with disorders of consciousness (DOC) classically receive hydration and nutrition through an enteral-feeding tube. However, the real impact of the level of consciousness on an individual's swallowing ability remains poorly investigated. OBJECTIVE: We aimed to document the incidence and characteristics of dysphagia in DOC individuals and to evaluate the link between different components of swallowing and the level of consciousness. METHODS: We analyzed clinical data on the respiratory status, oral feeding and otolaryngologic examination of swallowing in DOC individuals. We analyzed the association of components of swallowing and participant groups (i.e., unresponsive wakefulness syndrome [UWS] and minimally conscious state [MCS]). RESULTS: We included 92 individuals with DOC (26 UWS and 66 MCS). Overall, 99% of the participants showed deficits in the oral and/or pharyngeal phase of swallowing. As compared with the MCS group, the UWS group more frequently had a tracheostomy (69% vs 24%), with diminished cough reflex (27% vs 54%) and no effective oral phase (0% vs 21%). CONCLUSION: Almost all DOC participants had severe dysphagia. Some components of swallowing (i.e., tracheostomy, cough reflex and efficacy of the oral phase of swallowing) were related to consciousness. In particular, no UWS participant had an efficient oral phase, which suggests that its presence may be a sign of consciousness. In addition, no UWS participant could be fed entirely orally, whereas no MCS participant orally received ordinary food. Our study also confirms that objective swallowing assessment can be successfully completed in DOC individuals and that specific care is needed to treat severe dysphagia in DOC.

Subjective visual vertical in patients with Usher syndrome.

BACKGROUND: Verticality, or more precisely the ability to perceive spatial orientation with regard to gravity, is based on the integration of visual, vestibular and somesthetic information. OBJECTIVE: The purpose of the present study was to compare the subjective visual vertical (SVV) in patients with Usher (type I and type II) with visual or vestibular impairment, and in healthy participants, in order to explore the importance of the visual and vestibular functions on the vertical's perception. METHODS: We evaluated the SVV using a wall housing which projects on the opposite wall a red-light line of about 2 meters, obtained by laser cannon. The evaluation was carried out under two tilt conditions: clockwise and counter-clockwise randomly performed five times in each direction. The response to the SVV task was quantified by the mean of the absolute values of the SVV. RESULTS: Responses to the SVV were significantly less accurate in patients with Usher with respect to healthy participants while it was similar for the two groups of patients with Usher. CONCLUSIONS: We hypothesize that visual inputs play a very important role in the perception of verticality and that the symmetrical bilateral vestibular deficit in Usher type I does not have a strong impact in perception of verticality.

Tinnitus distress: a paradoxical attention to the sound?

Tinnitus, the perception of sound in the absence of external stimuli, is often a disturbing symptom for which the underlying functional neuroanatomy still remains poorly understood. Most studies have focused solely on functional connectivity changes in the auditory cortex of tinnitus patients. The aim of this study was to investigate whether a correlation exists between tinnitus behavioural scores and functional brain connectivity of five resting-state networks comprising the auditory, the default mode, the external control left and right, and the salience network. For this purpose, a large sample of one hundred and thirty-five subjects underwent resting-state functional magnetic resonance imaging and their behavioural scores were obtained using clinical evaluations. Networks were extracted using independent component analysis, and functional connectivity patterns in the extracted networks were evaluated by a graph theoretical approach. The effects of tinnitus for each network were investigated by correlating the graph strength of all the regions with the tinnitus behavioural scores using stepwise fit regression analysis. Results indicated that alterations of functional interactions between key neural circuits of the brain are not limited to one single network. In particular, tinnitus distress showed a strong correlation with the connectivity pattern within and between the right executive control network and the other four resting-state networks, indicating that tinnitus distress is probably the consequence of a hyperactive attention condition. Among the behavioural scores, the strongest correlation was observed between age and hearing loss, while the tinnitus objective loudness was not correlated with any behavioural scores.

Conscious While Being Considered in an Unresponsive Wakefulness Syndrome for 20 Years.

Despite recent advances in our understanding of consciousness disorders, accurate diagnosis of severely brain-damaged patients is still a major clinical challenge. We here present the case of a patient who was considered in an unresponsive wakefulness syndrome/vegetative state for 20 years. Repeated standardized behavioral examinations combined to neuroimaging assessments allowed us to show that this patient was in fact fully conscious and was able to functionally communicate. We thus revised the diagnosis into an incomplete locked-in syndrome, notably because the main brain lesion was located in the brainstem. Clinical examinations of severe brain injured patients suffering from serious motor impairment should systematically include repeated standardized behavioral assessments and, when possible, neuroimaging evaluations encompassing magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography.

Is oral feeding compatible with an unresponsive wakefulness syndrome?

OBJECTIVE: The aim of the study is to explore the possibility of oral feeding in unresponsive wakefulness syndrome/vegetative state (UWS/VS) patients. METHOD: We reviewed the clinical information of 68 UWS/VS patients (mean age 45 ± 11; range 16-79 years) searching for mention of oral feeding. UWS/VS diagnosis was made after repeated behavioural assessments using the Coma Recovery Scale-Revised. Patients also had complementary neuroimaging evaluations (positron emission tomography, functional magnetic resonance imaging and electroencephalography and diffusion tensor imaging). RESULTS: Out of the 68 UWS/VS patients, only two could resume oral feeding (3%). The first patient had oral feeding (only liquid and semi liquid) in addition to gastrostomy feeding and the second one could achieve full oral feeding (liquid and mixed solid food). Clinical assessments concluded that they fulfilled the criteria for a diagnosis of UWS/VS. Results from neuroimaging and neurophysiology were typical for the first patient with regard to the diagnosis of UWS/VS but atypical for the second patient. CONCLUSION: Oral feeding that implies a full and complex oral phase could probably be considered as a sign of consciousness. However, we actually do not know which components are necessary to consider the swallowing conscious as compared to reflex. We also discussed the importance of swallowing assessment and management in all patients with altered state of consciousness.

Frontostriatal Gating of Tinnitus and Chronic Pain.

Tinnitus and chronic pain are sensory-perceptual disorders associated with negative affect and high impact on well-being and behavior. It is now becoming increasingly clear that higher cognitive and affective brain systems are centrally involved in the pathology of both disorders. We propose that the ventromedial prefrontal cortex and the nucleus accumbens are part of a central 'gatekeeping' system in both sensory modalities, a system which evaluates the relevance and affective value of sensory stimuli and controls information flow via descending pathways. If this frontostriatal system is compromised, long-lasting disturbances are the result. Parallels in both systems are striking and mutually informative, and progress in understanding central gating mechanisms might provide a new impetus to the therapy of tinnitus and chronic pain.

Auditory resting-state network connectivity in tinnitus: a functional MRI study.

The underlying functional neuroanatomy of tinnitus remains poorly understood. Few studies have focused on functional cerebral connectivity changes in tinnitus patients. The aim of this study was to test if functional MRI "resting-state" connectivity patterns in auditory network differ between tinnitus patients and normal controls. Thirteen chronic tinnitus subjects and fifteen age-matched healthy controls were studied on a 3 tesla MRI. Connectivity was investigated using independent component analysis and an automated component selection approach taking into account the spatial and temporal properties of each component. Connectivity in extra-auditory regions such as brainstem, basal ganglia/NAc, cerebellum, parahippocampal, right prefrontal, parietal, and sensorimotor areas was found to be increased in tinnitus subjects. The right primary auditory cortex, left prefrontal, left fusiform gyrus, and bilateral occipital regions showed a decreased connectivity in tinnitus. These results show that there is a modification of cortical and subcortical functional connectivity in tinnitus encompassing attentional, mnemonic, and emotional networks. Our data corroborate the hypothesized implication of non-auditory regions in tinnitus physiopathology and suggest that various regions of the brain seem involved in the persistent awareness of the phenomenon as well as in the development of the associated distress leading to disabling chronic tinnitus.

Another kind of 'BOLD Response': answering multiple-choice questions via online decoded single-trial brain signals.

The term 'locked-in'syndrome (LIS) describes a medical condition in which persons concerned are severely paralyzed and at the same time fully conscious and awake. The resulting anarthria makes it impossible for these patients to naturally communicate, which results in diagnostic as well as serious practical and ethical problems. Therefore, developing alternative, muscle-independent communication means is of prime importance. Such communication means can be realized via brain-computer interfaces (BCIs) circumventing the muscular system by using brain signals associated with preserved cognitive, sensory, and emotional brain functions. Primarily, BCIs based on electrophysiological measures have been developed and applied with remarkable success. Recently, also blood flow-based neuroimaging methods, such as functional magnetic resonance imaging (fMRI) and functional near-infrared spectroscopy (fNIRS), have been explored in this context. After reviewing recent literature on the development of especially hemodynamically based BCIs, we introduce a highly reliable and easy-to-apply communication procedure that enables untrained participants to motor-independently and relatively effortlessly answer multiple-choice questions based on intentionally generated single-trial fMRI signals that can be decoded online. Our technique takes advantage of the participants' capability to voluntarily influence certain spatio-temporal aspects of the blood oxygenation level-dependent (BOLD) signal: source location (by using different mental tasks), signal onset and offset. We show that healthy participants are capable of hemodynamically encoding at least four distinct information units on a single-trial level without extensive pretraining and with little effort. Moreover, real-time data analysis based on simple multi-filter correlations allows for automated answer decoding with a high accuracy (94.9%) demonstrating the robustness of the presented method. Following our 'proof of concept', the next step will involve clinical trials with LIS patients, undertaken in close collaboration with their relatives and caretakers in order to elaborate individually tailored communication protocols. As our procedure can be easily transferred to MRI-equipped clinical sites, it may constitute a simple and effective possibility for online detection of residual consciousness and for LIS patients to communicate basic thoughts and needs in case no other alternative communication means are available (yet)--especially in the acute phase of the LIS. Future research may focus on further increasing the efficiency and accuracy of fMRI-based BCIs by implementing sophisticated data analysis methods (e.g., multivariate and independent component analysis) and neurofeedback training techniques. Finally, the presented BCI approach could be transferred to portable fNIRS systems as only this would enable hemodynamically based communication in daily life situations.

Human cognition during REM sleep and the activity profile within frontal and parietal cortices: a reappraisal of functional neuroimaging data.

In this chapter, we aimed at further characterizing the functional neuroanatomy of the human rapid eye movement (REM) sleep at the population level. We carried out a meta-analysis of a large dataset of positron emission tomography (PET) scans acquired during wakefulness, slow wave sleep and REM sleep, and focused especially on the brain areas in which the activity diminishes during REM sleep. Results show that quiescent regions are confined to the inferior and middle frontal cortex and to the inferior parietal lobule. Providing a plausible explanation for some of the features of dream reports, these findings may help in refining the concepts, which try to account for human cognition during REM sleep. In particular, we discuss the significance of these results to explain the alteration in executive processes, episodic memory retrieval and self representation during REM sleep dreaming as well as the incorporation of external stimuli into the dream narrative.