The dorsomedial hypothalamic nucleus and perifornical area (DMH/PeF), historically identified as the hypothalamic defence area, plays a key role in orchestrating autonomic and respiratory adjustments during threat-related states. To investigate how activation of this region affects upper-airway and respiratory motor circuits, we examined its anatomical and functional interactions with laryngeal-related medullary nuclei using combined immunohistochemical mapping and physiological recordings in spontaneously breathing anaesthetised rats. Neuronal activation was assessed using c-Fos immunohistochemistry (c-Fos-ir) combined with ChAT and FoxP2 labelling to identify motoneurons and non-motoneuronal populations across the compact, semicompact and loose formations of the nucleus ambiguus (nA), as well as within the nucleus retroambiguus (nRA), during DMH/PeF electrical stimulation. Hypothalamic activation produced a clear subdivision-specific recruitment in the nA, with significant ipsilateral increases in c-Fos-ir within the semicompact (motoneurons, p < 0.001; non-motoneurons, p < 0.05) and compact formations (non-motoneurons, p < 0.05). The nRA also exhibited robust ipsilateral activation (non-motoneurons, p < 0.001). FoxP2-positive neurons remained stable across groups, indicating that FoxP2 reflects neuronal phenotype rather than acute activation. A second set of experiments evaluated the functional impact of electrical and chemical (glutamate) DMH/PeF activation on subglottic pressure, an index of laryngeal resistance. Both stimulation modalities produced a marked reduction in subglottic pressure (p < 0.001 and p < 0.01), accompanied by a reproducible autonomic–respiratory pattern characterised by tachypnoea, tachycardia and a pressor response. Overall, our results provide new insight into how hypothalamic circuits regulate subglottic pressure and laryngeal activity, suggesting that DMH/PeF activation is associated with the recruitment of specific nA and nRA domains, which may contribute to the adjustment of upper-airway patency during defensive responses.
Verbal fluency after cochlear implantation: a longitudinal comparison with untreated hearing loss in the ELSA cohort
IntroductionHearing loss is associated with accelerated cognitive decline, and auditory rehabilitation via cochlear implantation (CI) may mitigate this trajectory. In the past, the impact of cochlear implantation on different cognitive subdomains has been described. However, verbal fluency (VF), which requires fast semantic retrieval, executive control, and processing speed, and is predictive of dementia risk and overall survival, has been rarely studied and control groups are mostly missing due to ethical reasons. The present study compares long-term VF trajectories in CI recipients and untreated hearing-impaired controls from a large population-based aging study.Materials and methodsVF was assessed in 74 CI recipients (M = 65.6 years, SD = 9.1) at pre-operative baseline and 1, 2, 4.5, and up to 9 years post-implantation, and in 383 untreated hearing-impaired participants (M = 72.6 years, SD = 10.0) from the English Longitudinal Study of Ageing (ELSA) across a comparable time frame. Scores were z-standardized within each study to enable cross-cohort comparison. Linear mixed-effects models were used to compare VF trajectories, with age, sex, and education as covariates.ResultsVF trajectories differed significantly between groups (Time × Study interaction: b = 0.562, p < 0.001). The ELSA cohort showed a steady linear decline over time (b = −0.261, p = 0.001), whereas the CI cohort exhibited an inverted-U trajectory with initial improvement followed by a plateau. After propensity score matching, results remained robust.ConclusionCochlear implantation is associated with more favorable long-term verbal fluency trajectories compared to untreated hearing loss. These findings add to the growing evidence that auditory rehabilitation may help preserve cognitive function in older adults.
Gerstmann-Sträussler-Scheinker syndrome with unexpected concomitant GRN variant: case report
The objective is to report a patient with Gerstmann-Sträussler-Scheinker syndrome caused by a pathogenic PRNP P102L variant harboring an unexpected concomitant pathogenic GRN variant p.R110X and to discuss the potential contribution of combined genetic pathology to the clinical and neuroimaging phenotype confirmed by autopsy. Moreover, we discuss the potential role of TMEM106B as an important modifier of the protein TDP-43 neuropathology associated with the GRN mutation in this case. The patient underwent detailed clinical assessment, serial neuropsychological evaluation, brain MRI, cerebrospinal fluid analysis, whole-exome sequencing, and next generation sequencing. A postmortem neuropathologic examination was performed to confirm the diagnosis. The patient presented slowly progressive paresthesia, cerebellar ataxia, dysarthria, and later cognitive and behavioral changes. Genetic testing revealed a heterozygous PRNP P102L variant and an unpenetrated GRN p.R110X variant; a protective TMEM106B polymorphism associated with TDP-43 pathology was also identified. Neuroimaging demonstrated progressive cerebellar and parietal atrophy with asymmetric left frontal opercular and insular involvement. The clinical course was dominated by a cerebellar GSS phenotype. The patient died 4 years after symptom onset. Neuropathology confirmed GSS, nevertheless without detectable TDP-43-associated neuropathology. This case highlights the diagnostic complexity of rare neurodegenerative disorders and illustrates that pathogenic variants may not influence phenotypic expression. Comprehensive genetic testing should be considered in atypical cases, as certain genetic variants may contribute to phenotypic variability and represent potential modifiers of phenotypic expression.
Automatic Speech Recognition and Acoustic Analysis for Dysarthria Assessment in Telerehabilitation: User-Centered Design and Usability Study
Background: Dysarthria is a frequent motor speech disorder following a stroke, affecting up to 42% of survivors and resulting in reduced speech intelligibility and diminished quality of life. Clinical assessments, such as the Frenchay Dysarthria Assessment, Second Edition (FDA-2), rely heavily on the subjective judgment of speech-language pathologists (SLPs), which limits comparability and scalability. Telepractice solutions have the potential to extend access to care, but validated digital tools that combine automatic analysis with clinically usable interfaces remain scarce. Objective: This study aimed to develop and evaluate a web-based application that integrates automatic speech recognition (ASR) and acoustic analysis into a user-centered dashboard for SLPs. Specifically, we investigated: (1) whether ASR can provide intelligibility scores comparable to those of human listeners; (2) the usability of the system in 2 iterative cycles with SLPs; and (3) the feasibility of presenting clinically relevant acoustic features to support telerehabilitation. Methods: A user-centered design process was followed, involving contextual inquiry, requirements gathering, prototype development, and iterative testing with SLPs. The analytical core of the prototype included an ASR module (Whisper Large-v3) to compute intelligibility scores, combining word error rate–based accuracy with sentence-level and word-level alignment. Phoneme-level error highlighting was implemented to identify frequent substitution or deletion patterns. In parallel, an acoustic module extracted clinically relevant measures, including fundamental frequency (mean and range), intensity (mean and variability), and vowel formants (F1–F2 space), supplemented by sustained phonation duration. A pilot validation compared ASR-based intelligibility scores with transcriptions from 8 lay listeners for 3 patients with dysarthria performing the Frenchay Dysarthria Assessment–2 word and sentence tasks. Usability was evaluated in 2 cycles with 8 and 4 SLPs, respectively, using the System Usability Scale and structured questionnaires. Results: In the pilot validation, ASR performance was comparable to, and in some cases better than, untrained human listeners for individuals with mild and moderate dysarthria, though performance declined with severe cases. Both usability cycles yielded excellent System Usability Scale scores (cycle 1: mean 88.4, SD 4.6; cycle 2: mean 91.7, SD 4.1). Core workflow elements, including navigation, session upload, and intelligibility score presentation, were consistently rated highly. Feedback evolved from bug reports and requests for clearer terminology in cycle 1 to suggestions for advanced analytic features in cycle 2, such as additional voice-quality indices and integrated note-taking. Conclusions: The prototype demonstrates that automatic intelligibility scoring and acoustic analysis can be integrated into a clinically usable, web-based dashboard. While current limitations include reliance on English-only phoneme analysis, limited advanced acoustic features, and lack of regulatory compliance, the application achieved excellent usability and shows promise for scalable telerehabilitation. Future work should expand multilingual support, incorporate additional acoustic measures, and validate the tool in larger clinical cohorts.
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Digital Technologies for Children With Hearing Impairments to Support Language Learning: Scoping Review
Background: Children with hearing impairments (HIs) have traditionally faced difficulties with language acquisition due to various factors, such as difficulties in accessing early intervention and therapy, among others. There is an opportunity for digital technology to address this problem; however, how different technologies can facilitate language acquisition, as well as the level of evidence, is not well understood. Objective: This study aimed to explore the types, roles, and outcomes of different digital technologies in supporting language development in children with HIs. Methods: Following Arksey and O’Malley’s framework for conducting a scoping review and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews), we systematically searched 6 online databases from 2014 to September 2024 for relevant studies on the role of digital technologies in supporting language learning among children with HIs (aged <18 years). Results: A total of 45 studies met the inclusion criteria. Mobile apps were the most frequently reported technologies, followed by digital books, extended reality, computer-based programs, and tangible or robotic tools. The most commonly used signed-language apps focus on vocabulary development and visual communication. Spoken language tools were less common but included augmentative and alternative communication (AAC) systems and auditory training apps. The efficacy outcomes of 12 studies included in this review showed that AAC-based apps had stronger effects on expressive language, pragmatic communication skills, and vocabulary development. These outcomes occurred when AAC-based apps were used in structured contexts with a therapist or parent. In contrast, signed language apps often reported narrower, word-level outcomes. Notably, relatively few interventions targeted early spoken language development, despite early childhood being a critical period for language acquisition. In addition, limited attention was given to visual design considerations related to user comfort, cultural relevance, and contextual adaptation. Conclusions: The evidence base reveals 3 structural patterns: the dominance of accessibility-driven mobile technologies; an imbalance between signed and spoken-language interventions, characterized by a greater number of signed-language tools but stronger and more consistent evidence for spoken-language outcomes, particularly in AAC-based interventions; and limited integration of digital technologies across home, school, and clinical contexts. Future research should prioritize the co-design and evaluation of culturally responsive, integrated, developmentally appropriate digital systems that support early spoken-language development and sustained, family-mediated language learning across contexts.
Association between plasma proBDNF levels and cognitive impairment in patients with alcohol dependence: a case–control and longitudinal study
BackgroundAlcohol dependence is frequently accompanied by cognitive impairment. Brain-derived neurotrophic factor (BDNF) signaling plays a critical role in synaptic plasticity, while the precursor form, proBDNF, has been increasingly implicated in neurodegenerative and psychiatric disorders. However, the association between plasma proBDNF levels and cognitive impairment in alcohol dependence remains unclear.MethodsEighty male patients with alcohol dependence and forty-two matched healthy controls were enrolled. Plasma proBDNF levels were measured via enzyme-linked immunosorbent assay (ELISA). Cognitive function was assessed using the Mini-Mental State Examination (MMSE), the Modified Wisconsin Card Sorting Test (M-WCST), and the Verbal Fluency Test (VFT). Forty-one patients were reassessed after four weeks of abstinence. Group comparisons and correlation analyses were performed.ResultsPatients with alcohol dependence exhibited significantly elevated plasma proBDNF levels and impaired cognitive performance compared with controls. Plasma proBDNF levels were positively correlated with alcohol consumption severity, and linked to global cognitive deficits alongside nuanced executive performance variations. After four weeks of abstinence, plasma proBDNF levels decreased and cognitive performance improved; however, changes in proBDNF were weakly associated with cognitive recovery.ConclusionsElevated plasma proBDNF levels are associated with alcohol dependence severity and cognitive impairment, suggesting that proBDNF may serve as a peripheral biomarker reflecting the dynamic neurocognitive status in alcohol dependence.
Cortical high-threshold and low-activation characteristics in adolescent depression: a cross-age differential analysis
BackgroundAdolescent depression exhibits distinct neurophysiological features, with marked age heterogeneity particularly in the resting motor threshold (RMT) measured during repetitive transcranial magnetic stimulation (rTMS), and substantial variability in clinical therapeutic efficacy. Functional near-infrared spectroscopy (fNIRS) enables the assessment of cortical excitability levels; however, research investigating the association between RMT and cortical activation in adolescent patients with depression remains limited. This study aims to elucidate the underlying neural mechanisms from the perspective of cortical hemodynamics, which is crucial for further optimizing neuromodulation strategies in patients with depression.MethodsWe collected data from 85 treatment-naive patients with depression who underwent rTMS therapy. All patients completed RMT measurement, fNIRS examination, and Hamilton Depression Rating Scale (HAMD) assessment prior to rTMS treatment. Participants were divided into three groups according to age: the adolescents group (n=31), the young adult group (n=26), and the middle-aged group (n=28). We compared the differences in RMT among the three groups and explored the relationships between RMT, cortical activation (reflected by prefrontal oxyhemoglobin level changes during the verbal fluency task via fNIRS), and depression severity (assessed by HAMD scores).ResultsThe results demonstrated that the adolescents group had a significantly higher RMT than the other age groups (58.00 ± 11.14, P < 0.001), accompanied by the lowest prefrontal Oxy-Hb activation level (0.095 ± 0.06, P < 0.001). A strong negative correlation was observed between RMT and cortical activation (Spearman’s rs= -0.929, P < 0.001), while a strong positive correlation was found between RMT and depression severity (Spearman’s rs = 0.837, P < 0.001). The distinct coupling phenomenon of high threshold-low activation-severe symptoms was most prominently manifested in this age group, which may theoretically reflect an underlying dysregulation in broader emotional networks, though the current direct findings strictly indicate localized alterations in prefrontal activation and motor cortical excitability.ConclusionsThe characteristics of high RMT and low cortical activation in adolescent depression serve as important neurobiological markers for depression severity. This finding provides a novel direction for developing individualized, developmentally tailored neuromodulation strategies (e.g., optimization of rTMS targets and dosages), indicating that interventions for adolescent depression should prioritize promoting the healthy integration of emotional circuits and the functional coordination between the cortex and subcortex.
Frontotemporal dementia: does structural MRI-based clustering match clinical syndromes?
BackgroundFrontotemporal dementia is an umbrella term that encompasses several clinical syndromes with impaired behavioral, language, and motor functions. These syndromes show considerable overlap in clinical features and imaging patterns. Therefore, there is a need to investigate the syndromic heterogeneity in FTD using unbiased data-driven approaches.MethodsWe used data-driven clustering analysis of structural magnetic resonance imaging (MRI) data on 400 patients with clinical FTD diagnoses [behavioral variant of frontotemporal dementia (bvFTD), semantic variant of primary progressive aphasia (svPPA), right temporal variant of frontotemporal dementia (rtvFTD), apraxia of speech with agrammatic aphasia (AOS-PAA), primary progressive apraxia of speech (PPAOS), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and primary progressive aphasia who did not fit into the other diagnostic categories (PPA-other)]. MR images were w-scored relative to cognitively unimpaired individuals, and principal component analysis was performed. A clustering ensemble approach, including hierarchical algorithms, was applied to the MR-based principal components, and imaging and clinical characteristics of the clusters were investigated. Various numbers of clusters (K = 2, 3, or 4) were evaluated.ResultsThe K = 3 solution offered the most clinically meaningful separation of FTD syndromes. The first cluster captured mostly frontal MRI abnormalities related to the speech, language and behavioral clinical dimensions, including patients with AOS-PAA, PPAOS, PPA-other, and bvFTD. The second cluster captured mostly temporal abnormalities and included mainly patients with svPPA and rtvFTD, but also bvFTD, AOS-PAA, and PPA-other. The third cluster captured cortical and subcortical atrophy, particularly in the midbrain, and included atypical Parkinsonian syndromes, with all PSP and CBS patients captured in this cluster, as well as most PPAOS patients. Considerable overlap of clinical syndromes was noted across these clusters, whereby patients with AOS-PAA, svPPA, PPA-other, and bvFTD were captured in more than one cluster.DiscussionOur findings highlight heterogeneity in FTD, which mainly exists along three axes: speech, language and behavioral deficits reflecting frontal atrophy, language deficits reflecting temporal atrophy, and motor and motor speech deficits reflecting mostly midbrain and subcortical atrophy, with cortical involvement.