Changes in visually and auditory attended audiovisual speech processing in cochlear implant users: A longitudinal ERP study.

Limited auditory input, whether caused by hearing loss or by electrical stimulation through a cochlear implant (CI), can be compensated by the remaining senses. Specifically for CI users, previous studies reported not only improved visual skills, but also altered cortical processing of unisensory visual and auditory stimuli. However, in multisensory scenarios, it is still unclear how auditory deprivation (before implantation) and electrical hearing experience (after implantation) affect cortical audiovisual speech processing. Here, we present a prospective longitudinal electroencephalography (EEG) study which systematically examined the deprivation- and CI-induced alterations of cortical processing of audiovisual words by comparing event-related potentials (ERPs) in postlingually deafened CI users before and after implantation (five weeks and six months of CI use). A group of matched normal-hearing (NH) listeners served as controls. The participants performed a word-identification task with congruent and incongruent audiovisual words, focusing their attention on either the visual (lip movement) or the auditory speech signal. This allowed us to study the (top-down) attention effect on the (bottom-up) sensory cortical processing of audiovisual speech. When compared to the NH listeners, the CI candidates (before implantation) and the CI users (after implantation) exhibited enhanced lipreading abilities and an altered cortical response at the N1 latency range (90-150 ms) that was characterized by a decreased theta oscillation power (4-8 Hz) and a smaller amplitude in the auditory cortex. After implantation, however, the auditory-cortex response gradually increased and developed a stronger intra-modal connectivity. Nevertheless, task efficiency and activation in the visual cortex was significantly modulated in both groups by focusing attention on the visual as compared to the auditory speech signal, with the NH listeners additionally showing an attention-dependent decrease in beta oscillation power (13-30 Hz). In sum, these results suggest remarkable deprivation effects on audiovisual speech processing in the auditory cortex, which partially reverse after implantation. Although even experienced CI users still show distinct audiovisual speech processing compared to NH listeners, pronounced effects of (top-down) direction of attention on (bottom-up) audiovisual processing can be observed in both groups. However, NH listeners but not CI users appear to show enhanced allocation of cognitive resources in visually as compared to auditory attended audiovisual speech conditions, which supports our behavioural observations of poorer lipreading abilities and reduced visual influence on audition in NH listeners as compared to CI users.

Efhamni: A Deep Learning-Based Saudi Sign Language Recognition Application.

Deaf and hard-of-hearing people mainly communicate using sign language, which is a set of signs made using hand gestures combined with facial expressions to make meaningful and complete sentences. The problem that faces deaf and hard-of-hearing people is the lack of automatic tools that translate sign languages into written or spoken text, which has led to a communication gap between them and their communities. Most state-of-the-art vision-based sign language recognition approaches focus on translating non-Arabic sign languages, with few targeting the Arabic Sign Language (ArSL) and even fewer targeting the Saudi Sign Language (SSL). This paper proposes a mobile application that helps deaf and hard-of-hearing people in Saudi Arabia to communicate efficiently with their communities. The prototype is an Android-based mobile application that applies deep learning techniques to translate isolated SSL to text and audio and includes unique features that are not available in other related applications targeting ArSL. The proposed approach, when evaluated on a comprehensive dataset, has demonstrated its effectiveness by outperforming several state-of-the-art approaches and producing results that are comparable to these approaches. Moreover, testing the prototype on several deaf and hard-of-hearing users, in addition to hearing users, proved its usefulness. In the future, we aim to improve the accuracy of the model and enrich the application with more features.

Electrically evoked auditory brainstem responses in deaf children with cochlear nerve canal stenosis.

BACKGROUND: Deaf children with cochlear nerve canal stenosis (CNCs) are always considered poor candidates for cochlear implantation. OBJECTIVES: To investigate the function of the peripheral auditory pathway in deaf children with CNCs, as revealed by the electrically evoked auditory brainstem response (EABR), and postoperative cochlear implants (CIs) outcomes. MATERIALS AND METHODS: Thirteen children with CNCs and 13 children with no inner ear malformations (IEMs) who received CIs were recruited. The EABR evoked by electrical stimulation from the CI electrode was recorded. Postoperative CI outcomes were assessed using Categories of Auditory Performance (CAP) and Speech Intelligibility Rate (SIR). RESULTS: Compared with children with no IEMs, children with CNCs showed lower EABR extraction rates, higher thresholds, a longer wave V (eV) latency and lower CAP and SIR scores. The auditory and speech performance was positively correlated with the diameter of the cochlear nerve canal and the number of channels showing wave III (eIII) and eV in children with CNCs. CONCLUSIONS AND SIGNIFICANCE: The physiological function of the peripheral auditory pathway in children with CNCs is poorer than that in children with no IEMs. Postoperative auditory and speech abilities may depend on the severity of cochlear nerve malformation and auditory conduction function.

Two are better than one: Differences in cortical EEG patterns during auditory and visual verbal working memory processing between Unilateral and Bilateral Cochlear Implanted children.

Despite the proven effectiveness of cochlear implant (CI) in the hearing restoration of deaf or hard-of-hearing (DHH) children, to date, extreme variability in verbal working memory (VWM) abilities is observed in both unilateral and bilateral CI user children (CIs). Although clinical experience has long observed deficits in this fundamental executive function in CIs, the cause to date is still unknown. Here, we have set out to investigate differences in brain functioning regarding the impact of monaural and binaural listening in CIs compared with normal hearing (NH) peers during a three-level difficulty n-back task undertaken in two sensory modalities (auditory and visual). The objective of this pioneering study was to identify electroencephalographic (EEG) marker pattern differences in visual and auditory VWM performances in CIs compared to NH peers and possible differences between unilateral cochlear implant (UCI) and bilateral cochlear implant (BCI) users. The main results revealed differences in theta and gamma EEG bands. Compared with hearing controls and BCIs, UCIs showed hypoactivation of theta in the frontal area during the most complex condition of the auditory task and a correlation of the same activation with VWM performance. Hypoactivation in theta was also observed, again for UCIs, in the left hemisphere when compared to BCIs and in the gamma band in UCIs compared to both BCIs and NHs. For the latter two, a correlation was found between left hemispheric gamma oscillation and performance in the audio task. These findings, discussed in the light of recent research, suggest that unilateral CI is deficient in supporting auditory VWM in DHH. At the same time, bilateral CI would allow the DHH child to approach the VWM benchmark for NH children. The present study suggests the possible effectiveness of EEG in supporting, through a targeted approach, the diagnosis and rehabilitation of VWM in DHH children.

Between bodily action and conventionalized structure: The neural mechanisms of constructed action in sign language comprehension.

Sign languages (SLs) are expressed through different bodily actions, ranging from re-enactment of physical events (constructed action, CA) to sequences of lexical signs with internal structure (plain telling, PT). Despite the prevalence of CA in signed interactions and its significance for SL comprehension, its neural dynamics remain unexplored. We examined the processing of different types of CA (subtle, reduced, and overt) and PT in 35 adult deaf or hearing native signers. The electroencephalographic-based processing of signed sentences with incongruent targets was recorded. Attenuated N300 and early N400 were observed for CA in deaf but not in hearing signers. No differences were found between sentences with CA types in all signers, suggesting a continuum from PT to overt CA. Deaf signers focused more on body movements; hearing signers on faces. We conclude that CA is processed less effortlessly than PT, arguably because of its strong focus on bodily actions.

A systematic review of altered resting-state networks in early deafness and implications for cochlear implantation outcomes.

Auditory deprivation following congenital/pre-lingual deafness (C/PD) can drastically affect brain development and its functional organisation. This systematic review intends to extend current knowledge of the impact of C/PD and deafness duration on brain resting-state networks (RSNs), review changes in RSNs and spoken language outcomes post-cochlear implant (CI) and draw conclusions for future research. The systematic literature search followed the PRISMA guideline. Two independent reviewers searched four electronic databases using combined keywords: 'auditory deprivation', 'congenital/prelingual deafness', 'resting-state functional connectivity' (RSFC), 'resting-state fMRI' and 'cochlear implant'. Seventeen studies (16 cross-sectional and one longitudinal) met the inclusion criteria. Using the Crowe Critical Appraisal Tool, the publications' quality was rated between 65.0% and 92.5% (mean: 84.10%), ≥80% in 13 out of 17 studies. A few studies were deficient in sampling and/or ethical considerations. According to the findings, early auditory deprivation results in enhanced RSFC between the auditory network and brain networks involved in non-verbal communication, and high levels of spontaneous neural activity in the auditory cortex before CI are evidence of occupied auditory cortical areas with other sensory modalities (cross-modal plasticity) and sub-optimal CI outcomes. Overall, current evidence supports the idea that moreover intramodal and cross-modal plasticity, the entire brain adaptation following auditory deprivation contributes to spoken language development and compensatory behaviours.

Association of Hearing Loss With Anatomical and Functional Connectivity in Patients With Mild Cognitive Impairment.

Importance: Hearing loss is the most important modifiable risk factor for cognitive impairment; however, the association of hearing loss with anatomical and functional connectivity is not fully understood. This association may be elucidated by evaluating the findings of newer imaging technologies. Objectives: To evaluate the association of hearing loss with anatomical and functional connectivity in patients with mild cognitive impairment (MCI) by using multimodal imaging technology. Design, Setting, and Participants: This was a prospective cross-sectional study of patients with MCI under the care of a neurology clinic at the Soonchunhyang University Bucheon Hospital (Republic of Korea) from April to September 2021. Data were analyzed from April 1 to June 30, 2022. Main Outcomes and Measures: Pure tone averages (PTA) and word recognition scores were used to measure hearing acuity. Magnetic resonance imaging (MRI) and positron emission tomography scans of the brain were used to assess functional and anatomical connectivity. Results of diffusion MRI, voxel- and surface-based morphometric imaging, and global brain amyloid standardized uptake ratio were analyzed. Neuroimaging parameters of patients with MCI plus hearing loss were compared with those of patients with MCI and no hearing loss. Correlation analyses among neuroimaging parameters, PTA, and word recognition scores were performed. Results: Of 48 patients with MCI, 30 (62.5%) had hearing loss (PTA >25 dB) and 18 (37.5%) did not (PTA ≤25 dB). Median (IQR) age was 73.5 (69.0-78.0) years in the group with hearing loss and 75.0 (65.0-78.0) years in the group with normal hearing; there were 20 (66.7%) and 14 (77.8%) women in each group, respectively. The group with MCI plus hearing loss demonstrated decreased functional connectivity between the bilateral insular and anterior divisions of the cingulate cortex, and decreased fractional anisotropy in the bilateral fornix, corpus callosum forceps major and tapetum, left parahippocampal cingulum, and left superior thalamic radiation. Fractional anisotropy in the corpus callosum forceps major and bilateral parahippocampal cingulum negatively correlated with the severity of hearing loss shown by PTA testing. The 2 groups were not significantly different in global ß-amyloid uptake, gray matter volume, and cortical thickness. Conclusion and Relevance: The findings of this prospective cross-sectional study suggest that alterations in the salience network may contribute to the neural basis of cognitive impairment associated with hearing loss in patients who are on the Alzheimer disease continuum.

How (and why) does iconicity effect lexical access: An electrophysiological study of American sign language.

Prior research has found that iconicity facilitates sign production in picture-naming paradigms and has effects on ERP components. These findings may be explained by two separate hypotheses: (1) a task-specific hypothesis that suggests these effects occur because visual features of the iconic sign form can map onto the visual features of the pictures, and (2) a semantic feature hypothesis that suggests that the retrieval of iconic signs results in greater semantic activation due to the robust representation of sensory-motor semantic features compared to non-iconic signs. To test these two hypotheses, iconic and non-iconic American Sign Language (ASL) signs were elicited from deaf native/early signers using a picture-naming task and an English-to-ASL translation task, while electrophysiological recordings were made. Behavioral facilitation (faster response times) and reduced negativities were observed for iconic signs (both prior to and within the N400 time window), but only in the picture-naming task. No ERP or behavioral differences were found between iconic and non-iconic signs in the translation task. This pattern of results supports the task-specific hypothesis and provides evidence that iconicity only facilitates sign production when the eliciting stimulus and the form of the sign can visually overlap (a picture-sign alignment effect).

Effects of proprioception and core stability training followed by detraining on balance performance in deaf male students: a three-arm randomized controlled trial.

PURPOSE: Children with hearing impairment are unable to speak and may suffer from some physical problems such as weakness in postural performance ability and development. The aim of the current study was to explore the effects of proprioception versus core stability training for an 8-week period followed by a 6-month detraining protocol on the balance performance of deaf students. MATERIALS AND METHODS: This is a randomized controlled trial design of three groups in blinded evaluators. The study was conducted at the school gym. A total of 30 participants, of male deaf students, were randomized into three groups: (1) one group receiving proprioception training (PT, n = 10), (2), one group receiving core stability training (CST, n = 10) for 8 weeks, and (3), and control group (CON, n = 10). The Balance Error Scoring System (BESS) test and Y-balance test assess static and dynamic balance at pre- and post-training following a 6-month detraining. RESULTS: Post 8 weeks of training intervention, PT and CST values showed significant improvements in both static (p = 0.001) and dynamic (p = 0.001) balance. Following the 6-month detraining, only the PT group maintained their improvements in both the static and dynamic balance tests (p = 0.348) and the CST group showed decreases in the balance tests (p = 0.034). CONCLUSIONS: The results indicate that 8 weeks rehabilitation program (PT and CST) is an optimum training modality to enhance balance in deaf students and PT induces more training effects than CST for maintaining training benefits following the detraining. Clinical trial registry number: IRCT20170312033029N2; URL: https://en.irct.ir/trial/25584; Trial Id: 25584; Registration date: 2017-12-08; Study start date; 2017-12-22.

Locus coeruleus activity improves cochlear implant performance.

Cochlear implants (CIs) are neuroprosthetic devices that can provide hearing to deaf people1. Despite the benefits offered by CIs, the time taken for hearing to be restored and perceptual accuracy after long-term CI use remain highly variable2,3. CI use is believed to require neuroplasticity in the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to the variability in outcomes4-7. Despite extensive studies on how CIs activate the auditory system4,8-12, the understanding of CI-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator noradrenaline from the brainstem locus coeruleus (LC). Here we examine behavioural responses and neural activity in LC and auditory cortex of deafened rats fitted with multi-channel CIs. The rats were trained on a reward-based auditory task, and showed considerable individual differences of learning rates and maximum performance. LC photometry predicted when CI subjects began responding to sounds and longer-term perceptual accuracy. Optogenetic LC stimulation produced faster learning and higher long-term accuracy. Auditory cortical responses to CI stimulation reflected behavioural performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically relevant target for optimizing neuroprosthetic device use.

Visual form of ASL verb signs predicts non-signer judgment of transitivity.

Longstanding cross-linguistic work on event representations in spoken languages have argued for a robust mapping between an event's underlying representation and its syntactic encoding, such that-for example-the agent of an event is most frequently mapped to subject position. In the same vein, sign languages have long been claimed to construct signs that visually represent their meaning, i.e., signs that are iconic. Experimental research on linguistic parameters such as plurality and aspect has recently shown some of them to be visually universal in sign, i.e. recognized by non-signers as well as signers, and have identified specific visual cues that achieve this mapping. However, little is known about what makes action representations in sign language iconic, or whether and how the mapping of underlying event representations to syntactic encoding is visually apparent in the form of a verb sign. To this end, we asked what visual cues non-signers may use in evaluating transitivity (i.e., the number of entities involved in an action). To do this, we correlated non-signer judgments about transitivity of verb signs from American Sign Language (ASL) with phonological characteristics of these signs. We found that non-signers did not accurately guess the transitivity of the signs, but that non-signer transitivity judgments can nevertheless be predicted from the signs' visual characteristics. Further, non-signers cue in on just those features that code event representations across sign languages, despite interpreting them differently. This suggests the existence of visual biases that underlie detection of linguistic categories, such as transitivity, which may uncouple from underlying conceptual representations over time in mature sign languages due to lexicalization processes.

Sound source localization patterns and bilateral cochlear implants: Age at onset of deafness effects.

The ability to determine a sound's location is critical in everyday life. However, sound source localization is severely compromised for patients with hearing loss who receive bilateral cochlear implants (BiCIs). Several patient factors relate to poorer performance in listeners with BiCIs, associated with auditory deprivation, experience, and age. Critically, characteristic errors are made by patients with BiCIs (e.g., medial responses at lateral target locations), and the relationship between patient factors and the type of errors made by patients has seldom been investigated across individuals. In the present study, several different types of analysis were used to understand localization errors and their relationship with patient-dependent factors (selected based on their robustness of prediction). Binaural hearing experience is required for developing accurate localization skills, auditory deprivation is associated with degradation of the auditory periphery, and aging leads to poorer temporal resolution. Therefore, it was hypothesized that earlier onsets of deafness would be associated with poorer localization acuity and longer periods without BiCI stimulation or older age would lead to greater amounts of variability in localization responses. A novel machine learning approach was introduced to characterize the types of errors made by listeners with BiCIs, making them simple to interpret and generalizable to everyday experience. Sound localization performance was measured in 48 listeners with BiCIs using pink noise trains presented in free-field. Our results suggest that older age at testing and earlier onset of deafness are associated with greater average error, particularly for sound sources near the center of the head, consistent with previous research. The machine learning analysis revealed that variability of localization responses tended to be greater for individuals with earlier compared to later onsets of deafness. These results suggest that early bilateral hearing is essential for best sound source localization outcomes in listeners with BiCIs.

Naturalistic Use of Aspect Morphology in Deaf and Hard-of-Hearing Children.

Grammatical morphology often links small acoustic forms to abstract semantic domains. Deaf and hard-of-hearing (DHH) children have reduced access to the acoustic signal and frequently have delayed acquisition of grammatical morphology (e.g., Tomblin, Harrison, Ambrose, Walker, Oleson & Moeller, 2015). This study investigated the naturalistic use of aspectual morphology in DHH children to determine if they organize this semantic domain as normal hearing (NH) children have been found to do. Thirty DHH children (M = 6;8) and 29 NH children (M = 5;11) acquiring English participated in a free-play session and their tokens of perfective (simple past) and imperfective (-ing) morphology were coded for the lexical aspect of the predicate they marked. Both groups showed established prototype effects, favoring perfective + telic and imperfective + atelic pairings over perfective + atelic and perfective + atelic ones. Thus, despite reduced access to the acoustic signal, this DHH group was unimpaired for aspectual organization.

Reduced flash lag illusion in early deaf individuals.

When a brief flash is quickly presented aligned with a moving target, the flash typically appears to lag behind the moving stimulus. This effect is widely known in the literature as a flash-lag illusion (FLI). The flash-lag is an example of a motion-induced position shift. Since auditory deprivation leads to both enhanced visual skills and impaired temporal abilities, both crucial for the perception of the flash-lag effect, here we hypothesized that lack of audition could influence the FLI. 13 early deaf and 18 hearing individuals were tested in a visual FLI paradigm to investigate this hypothesis. As expected, results demonstrated a reduction of the flash-lag effect following early deafness, both in the central and peripheral visual fields. Moreover, only for deaf individuals, there is a positive correlation between the flash-lag effect in the peripheral and central visual field, suggesting that the mechanisms underlying the effect in the center of the visual field expand to the periphery following deafness. Overall, these findings reveal that lack of audition early in life profoundly impacts early visual processing underlying the flash-lag effect.

Prevalence and Clinical Characteristics of Hearing Loss Caused by MYH14 Variants.

Variants in MYH14 are reported to cause autosomal dominant nonsyndromic hereditary hearing loss (ADNSHL), with 34 variants reported to cause hearing loss in various ethnic groups. However, the available information on prevalence, as well as with regard to clinical features, remains fragmentary. In this study, genetic screening for MYH14 variants was carried out using a large series of Japanese hearing-loss patients to reveal more detailed information. Massively parallel DNA sequencing of 68 target candidate genes was applied in 8074 unrelated Japanese hearing-loss patients (including 1336 with ADNSHL) to identify genomic variations responsible for hearing loss. We identified 11 families with 10 variants. The prevalence was found to be 0.14% (11/8074) among all hearing-loss patients and 0.82% (11/1336) among ADNSHL patients. Nine of the eleven variants identified were novel. The patients typically showed late-onset hearing loss arising later than 20 years of age (64.3%, 9/14) along with progressive (92.3%, 12/13), moderate (62.5%, 10/16), and flat-type hearing loss (68.8%, 11/16). We also confirmed progressive hearing loss in serial audiograms. The clinical information revealed by the present study will contribute to further diagnosis and management of MYH14-associated hearing loss.

Mitochondrial Strokes: Diagnostic Challenges and Chameleons.

Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected in anyone with an acute/subacute onset of focal neurological symptoms at any age and are usually driven by seizures. Suggestive features of an underlying mitochondrial pathology include evolving MRI lesions, often originating within the posterior brain regions, the presence of multisystemic involvement, including diabetes, deafness, or cardiomyopathy, and a positive family history. The diagnosis of MELAS has important implications for those affected and their relatives, given it enables early initiation of appropriate treatment and genetic counselling. However, the diagnosis is frequently challenging, particularly during the acute phase of an event. We describe four cases of mitochondrial strokes to highlight the considerable overlap that exists with other neurological disorders, including viral and autoimmune encephalitis, ischemic stroke, and central nervous system (CNS) vasculitis, and discuss the clinical, laboratory, and imaging features that can help distinguish MELAS from these differential diagnoses.

Comprehensive functional network analysis and screening of deleterious pathogenic variants in non-syndromic hearing loss causative genes.

Hearing loss (HL) is a significant public health problem and causes the most frequent congenital disability in developed societies. The genetic analysis of non-syndromic hearing loss (NSHL) may be considered as a complement to the existent plethora of diagnostic modalities available. The present study focuses on exploring more target genes with respective non-synonymous single nucleotide polymorphisms (nsSNPs) involved in the development of NSHL. The functional network analysis and variant study have successfully been carried out from the gene pool retrieved from reported research articles of the last decade. The analyses have been done through STRING. According to predicted biological processes, various variant analysis tools have successfully classified the NSHL causative genes and identified the deleterious nsSNPs, respectively. Among the predicted pathogenic nsSNPs with rsIDs rs80356586 (I515T), rs80356596 (L1011P), rs80356606 (P1987R) in OTOF have been reported in NSHL earlier. The rs121909642 (P722S), rs267606805 (P722H) in FGFR1, rs121918506 (E565A) and rs121918509 (A628T, A629T) in FGFR2 have not been reported in NSHL yet, which should be clinically experimented in NSHL. This also indicates this variant's novelty as its association in NSHL. The findings and the analyzed data have delivered some vibrant genetic pathogenesis of NSHL. These data might be used in the diagnostic and prognostic purposes in non-syndromic congenitally deaf children.

An L1 retrotransposon insertion-induced deafness mouse model for studying the development and function of the cochlear stria vascularis.

Dysregulation of ion and potential homeostasis in the scala media is the most prevalent cause of hearing loss in mammals. However, it is not well understood how the development and function of the stria vascularis regulates this fluid homeostasis in the scala media. From a mouse genetic screen, we characterize a mouse line, named 299, that displays profound hearing impairment. Histology suggests that 299 mutant mice carry a severe, congenital structural defect of the stria vascularis. The in vivo recording of 299 mice using double-barreled electrodes shows that endocochlear potential is abolished and potassium concentration is reduced to ∼20 mM in the scala media, a stark contrast to the +80 mV endocochlear potential and the 150 mM potassium concentration present in healthy control mice. Genomic analysis revealed a roughly 7-kb-long, interspersed nuclear element (LINE-1 or L1) retrotransposon insertion on chromosome 11. Strikingly, the deletion of this L1 retrotransposon insertion from chromosome 11 restored the hearing of 299 mutant mice. In summary, we characterize a mouse model that enables the study of stria vascularis development and fluid homeostasis in the scala media.

A familial Danish dementia rat shows impaired presynaptic and postsynaptic glutamatergic transmission.

Familial British dementia and familial Danish dementia are neurodegenerative disorders caused by mutations in the gene integral membrane protein 2B (ITM2b) encoding BRI2, which tunes excitatory synaptic transmission at both presynaptic and postsynaptic termini. In addition, BRI2 interacts with and modulates proteolytic processing of amyloid-ß precursor protein (APP), whose mutations cause familial forms of Alzheimer's disease (AD) (familial AD). To study the pathogenic mechanisms triggered by the Danish mutation, we generated rats carrying the Danish mutation in the rat Itm2b gene (Itm2bD rats). Given the BRI2/APP interaction and the widely accepted relevance of human amyloid ß (Aß), a proteolytic product of APP, to AD, Itm2bD rats were engineered to express two humanized App alleles and produce human Aß. Here, we studied young Itm2bD rats to investigate early pathogenic changes in these diseases. We found that periadolescent Itm2bD rats not only present subtle changes in human Aß levels along with decreased spontaneous glutamate release and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated responses but also had increased short-term synaptic facilitation in the hippocampal Schaeffer-collateral pathway. These alterations in excitatory interneuronal communication can impair learning and memory processes and were akin to those observed in adult mice producing rodent Aß and carrying either the Danish or British mutations in the mouse Itm2b gene. Collectively, the data show that the pathogenic Danish mutation alters the physiological function of BRI2 at glutamatergic synapses across species and early in life. Future studies will determine whether this phenomenon represents an early pathogenic event in human dementia.

Patient Report of Hearing in Neurofibromatosis Type 2: Recommendations for Clinical Trials.

OBJECTIVE: To systematically evaluate published patient-reported outcome measures for the assessment of hearing function and hearing-related quality of life (QoL) and recommend measures selected by the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration (REiNS) as endpoints for clinical trials in neurofibromatosis type 2 (NF2). METHODS: The REiNS Patient-Reported Outcomes Working Group systematically evaluated published patient-reported outcome measures of (1) hearing function and (2) hearing-related QoL for individuals with hearing loss of various etiologies using previously published REiNS rating procedures. Ten measures of hearing functioning and 11 measures of hearing-related QoL were reviewed. Measures were numerically scored and compared primarily on their participant characteristics (including participant age range and availability of normative data), item content, psychometric properties, and feasibility for use in clinical trials. RESULTS: The Self-Assessment of Communication and the Self-Assessment of Communication-Adolescent were identified as most useful for adult and pediatric populations with NF2, respectively, for the measurement of both hearing function and hearing-related QoL. Measures were selected for their strengths in participant characteristics, item content, psychometric properties, and feasibility for use in clinical trials. CONCLUSIONS: REiNS recommends the Self-Assessment of Communication adult and adolescent forms for the assessment of patient-reported hearing function and hearing-related QoL for NF2 clinical trials. Further work is needed to demonstrate the utility of these measures in evaluating pharmacologic or behavioral interventions.