Search Results (49)

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder frequently associated with impairments in executive functions (EF). These deficits have been linked to difficulties across various cognitive domains, including metaphonological skills (MS), essential for phonological awareness and processing abilities. Background/Objectives: This pilot study examines the correlations between EF and MS in ADHD children. Methods: A total of 84 children aged 6–14 years, diagnosed with ADHD and an IQ ≥ 70, were assessed using the NEPSY-II test to evaluate executive functions and the Assessment of Metaphonological Skills Test to assess phonological processing abilities. Results: Correlational analyses and multiple regression models were employed to explore the relationships between EF and MS, focusing on attention, cognitive flexibility, and response inhibition. Rhyme was positively correlated with processing speed and negatively correlated with response inhibition. Phonemic segmentation was significantly related to auditory attention and response inhibition. Age emerged as a significant predictor of phonemic synthesis and final syllable deletion, consistent with the developmental maturation of executive and phonological abilities. Conclusions: The findings suggest that deficits in executive functioning in ADHD children are closely linked to metaphonological abilities, which play a crucial role in the acquisition of reading and writing skills. Integrating EF training into phonological interventions can help reduce learning difficulties and improve cognitive and language outcomes. Full article

Disabling hearing loss affects more than 5% of the global population, with numbers expected to double by 2050. The burden is especially high in low- and middle-income countries, where access to cochlear implant (CI) technology and the required follow-up care is limited. While CIs are a proven treatment for certain types of hearing loss, their adoption in these countries is hindered by high costs, the need for specialised rehabilitation, and the financial and time commitment required for long-term device maintenance. Although remote programming has improved accessibility to standard care, specialised interventions for complications remain restricted mainly to areas with clinical centres. Computational modelling offers a promising solution to this access-to-care dilemma. The models may be used to simulate complications, such as non-auditory stimulation (NAS), to investigate and plan personalised interventions, and ultimately predict device parameters, without requiring the recipient’s physical presence. Both phenomenological and biophysical models have already demonstrated useful application in CIs: the former streamlines clinical workflows and aims to establish consistency in device fitting, and the latter provides insights into patient-specific auditory biophysiology. Despite decades of research, clinical translation of biophysical models has been limited by data constraints, parameter uncertainty, and validation challenges. In this perspective piece, it is argued that biophysical models have now reached sufficient maturity to be integrated into routine CI care. Apart from the advantages that this approach will bring to the overall advancement of person-centred CI care, it is envisioned to improve accessibility, personalisation, and long-term outcomes for CI recipients in low- and middle-income countries. Full article

Hearing loss and serotonergic dysfunction both impact social and cognitive behaviors, yet their neurobiological interplay remains poorly understood. This study investigated whether perinatal fluoxetine exposure alters myelination in (auditory) brain regions during development. Female Wistar rats received 10 mg/kg fluoxetine from gestational day 1 until postnatal day (PND)21. Brain tissue was collected from male offspring at PND21 and PND35. Myelination was assessed via immunohistochemical analysis of Myelin-Associated Glycoprotein (MAG) and Myelin Basic Protein (MBP) in the auditory cortex, inferior colliculus, and corpus callosum. MAG+ cell counts, MBP+ area, and MBP fluorescence intensity were quantified. No major effects of fluoxetine were observed on myelin markers in any brain region or developmental stage. However, changes in myelination emerged between PND21 and PND35. MAG+ cell density declined in the inferior colliculus but remained stable in the auditory cortex. MBP+ area decreased over time in both the corpus callosum and auditory cortex, while MBP fluorescence intensity increased in the corpus callosum. These results suggest that myelination changes between PND21 and PND35 are region- and age-dependent and not altered by fluoxetine. These findings highlight the dynamic nature of postnatal myelination and suggest that serotonergic alterations alone may be insufficient to disrupt structural maturation in auditory regions. Full article

Background: Kölliker’s organ (KO), a transient structure in the cochlea, plays a critical role in the auditory maturation of mammals, particularly during embryonic and early postnatal development. This organ is essential for the proper differentiation and function of cochlear cells, acting as a pivotal source of signalling molecules that influence hair cell development and synaptic connectivity. Methods: This study systematically analyses the literature according to the PRISMA statement in order to evaluate the function roles of KO during cochlea development, reporting the molecular mechanisms and signalling pathways involved. Results: From our study, it emerged that KO supporting cells release adenosine triphosphate (ATP) through connexin hemichannels, initiating a cascade of intracellular calcium (Ca²⁺) signalling in adjacent inner hair cells (IHCs). This signalling promotes the release of glutamate, facilitating synaptic excitation of afferent nerve fibres and enhancing auditory neuron maturation prior to the onset of hearing. Additionally, the spontaneous electrical activity generated within KO supports the establishment of essential neural connections in the auditory pathway. The dynamic interplay between ATP release, Ca²⁺ signalling, and morphological changes in KO is crucial for cochlear compartmentalisation and fluid regulation, contributing to the formation of endolymph and perilymph. Furthermore, KO supports cellular plasticity and may provide a reservoir of precursor cells capable of trans-differentiating into hair cells under specific conditions. Conclusions: Dysregulation of KO function or delayed degeneration of its supporting cells has been implicated in auditory disorders, underscoring the importance of this organ in normal cochlear development and auditory function. Despite its identification over a century ago, further investigation is necessary to elucidate the molecular mechanisms underlying KO’s contributions to auditory maturation, particularly in human physiology. Full article

Background/Objectives: The cortical auditory evoked potential P1 response is a biomarker of cortical auditory maturation for tracking longitudinal cortical maturation in children with hearing loss after treatment with hearing aids and/or cochlear implants. In conjunction with hearing treatments, children with hearing loss commonly receive language therapy services. However, the effect of language therapy on cortical maturation in hearing loss is less well studied. Methods: This study explored auditory cortical maturation changes, using the P1 response, with coinciding language changes, utilizing the Preschool Language Scales test, following approximately six months of supplemental listening and spoken language therapy services in 39 children with hearing aids or cochlear implants. Results: Following supplemental language therapy, P1 latencies significantly decreased in all children, at a rate found to be significantly faster than expected for typical maturation. Language scores also significantly improved beyond expected maturation effects and were correlated with P1 latencies following supplemental therapy. Overall, with approximately six months of therapy, the children in this study made significantly greater gains of 9 to 10 months in total language and expressive communication. A subgroup analysis revealed that children with cochlear implants showed significantly lower language scores than their chronological age following supplemental therapy, while children with hearing aids obtained language scores that were not significantly different to their chronological age at follow-up. Conclusions: Overall, the results from this study showed that supplemental language therapy resulted in more typical auditory cortical maturation and improved language abilities and that the P1 CAEP response can objectively track neuroplastic changes in children as a function of language therapy provided in conjunction with hearing aids and CIs. Full article

Neonatal hyperbilirubinemia may result in long-lasting motor, auditory and learning impairments. The mechanisms responsible for the localization of unconjugated bilirubin (UCB) to specific brain areas as well as those involved in potentially permanent central nervous system (CNS) dysfunctions are far from being clear. One area of investigation includes exploring how hyperbilirubinemia determines neuronal alterations predisposing to neurodevelopmental disorders. We focused on the hippocampus and pyramidal cell dysregulation of calcium homeostasis and synaptic activity, with a particular focus on early forms of correlated network activity, i.e., giant depolarizing potentials (GDPs), crucially involved in shaping mature synaptic networks. We performed live calcium imaging and patch clamp recordings from acute hippocampal slices isolated from wild-type rats exposed to exogenous high bilirubin concentration. We then explored the impact of endogenous bilirubin accumulation in hippocampal slices isolated from a genetic model of hyperbilirubinemia, i.e., Gunn rats. Our data show in both models an age-dependent dysregulation of calcium dynamics accompanied by severe alterations in GDPs, which were strongly reduced in hippocampal slices of hyperbilirubinemic rats, where the expression of GABAergic neurotransmission markers was also altered. We propose that hyperbilirubinemia damages neurons and affects the refinement of GABAergic synaptic circuitry during a critical period of hippocampal development. Full article

Neurotrophins are proteins that mediate neuronal development using spatiotemporal signaling gradients. The chicken nucleus magnocellularis (NM), an analogous structure to the mammalian anteroventral cochlear nucleus, provides a model system in which signaling between the brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) is temporally regulated. In the NM, TrkB expression is high early in development (embryonic [E] day 9) and is downregulated until maturity (E18–21). It is currently unknown how BDNF–TrkB signaling affects neuronal properties throughout development and across a spatial (i.e., frequency) axis. To investigate this, we exogenously applied BDNF onto NM neurons ex vivo and studied intrinsic properties using whole-cell patch clamp electrophysiology. Early in development (E13), when TrkB expression is detectable with immunohistochemistry, BDNF application slowed the firing of high-frequency NM neurons, resembling an immature phenotype. Current measurements and biophysical modeling revealed that this was mediated by a decreased conductance of the voltage-dependent potassium channels. Interestingly, this effect was seen only in high-frequency neurons and not in low-frequency neurons. BDNF–TrkB signaling induced minimal changes in late-developing NM neurons (E20–21) of high and low frequencies. Our results indicate that normal developmental downregulation of BDNF–TrkB signaling promotes neuronal maturation tonotopically in the auditory brainstem, encouraging the appropriate development of neuronal properties. Full article

Sensorineural hearing loss (SNHL) is a prevalent and growing global health concern, especially within operational medicine, with limited therapeutic options available. This review article explores the emerging field of in vitro otic organoids as a promising platform for modeling hearing loss and developing novel therapeutic strategies. SNHL primarily results from the irreversible loss or dysfunction of cochlear mechanosensory hair cells (HCs) and spiral ganglion neurons (SGNs), emphasizing the need for innovative solutions. Current interventions offer symptomatic relief but do not address the root causes. Otic organoids, three-dimensional multicellular constructs that mimic the inner ear’s architecture, have shown immense potential in several critical areas. They enable the testing of gene therapies, drug discovery for sensory cell regeneration, and the study of inner ear development and pathology. Unlike traditional animal models, otic organoids closely replicate human inner ear pathophysiology, making them invaluable for translational research. This review discusses methodological advances in otic organoid generation, emphasizing the use of human pluripotent stem cells (hPSCs) to replicate inner ear development. Cellular and molecular characterization efforts have identified key markers and pathways essential for otic organoid development, shedding light on their potential in modeling inner ear disorders. Technological innovations, such as 3D bioprinting and microfluidics, have further enhanced the fidelity of these models. Despite challenges and limitations, including the need for standardized protocols and ethical considerations, otic organoids offer a transformative approach to understanding and treating auditory dysfunctions. As this field matures, it holds the potential to revolutionize the treatment landscape for hearing and balance disorders, moving us closer to personalized medicine for inner ear conditions. Full article

Kinase D-interacting substrate of 220 kDa (Kidins220) is a transmembrane protein that participates in neural cell survival, maturation, and plasticity. Mutations in the human KIDINS220 gene are associated with a neurodevelopmental disorder (‘SINO’ syndrome) characterized by spastic paraplegia, intellectual disability, and in some cases, autism spectrum disorder. To better understand the pathophysiology of KIDINS220-linked pathologies, in this study, we assessed the sensory processing and social behavior of transgenic mouse lines with reduced Kidins220 expression: the CaMKII-driven conditional knockout (cKO) line, lacking Kidins220 in adult forebrain excitatory neurons, and the Kidins220floxed line, expressing constitutively lower protein levels. We show that alterations in Kidins220 expression levels and its splicing pattern cause impaired response to both auditory and olfactory stimuli. Both transgenic lines show impaired startle response to high intensity sounds, with preserved pre-pulsed inhibition, and strongly reduced social odor recognition. In the Kidins220floxed line, olfactory alterations are associated with deficits in social memory and increased aggressive behavior. Our results broaden our knowledge of the SINO syndrome; understanding sensory information processing and its deviations under neuropathological conditions is crucial for devising future therapeutic strategies to enhance the quality of life of affected individuals. Full article

Gangliosides are major glycans on vertebrate nerve cells, and their metabolic disruption results in congenital disorders with marked cognitive and motor deficits. The sialyltransferase gene St3gal2 is responsible for terminal sialylation of two prominent brain gangliosides in mammals, GD1a and GT1b. In this study, we analyzed the expression of calcium-binding interneurons in primary sensory (somatic, visual, and auditory) and motor areas of the neocortex, hippocampus, and striatum of St3gal2-null mice as well as St3gal3-null and St3gal2/3-double null. Immunohistochemistry with highly specific primary antibodies for GABA, parvalbumin, calretinin, and calbindin were used for interneuron detection. St3gal2-null mice had decreased expression of all three analyzed types of calcium-binding interneurons in all analyzed regions of the neocortex. These results implicate gangliosides GD1a and GT1b in the process of interneuron migration and maturation. Full article

A significant portion of hearing-impaired children have additional disabilities, but data about the maturation of their auditory cortex are scarce. In these children, behavioral tests are often unreliable, and objective tests are needed for diagnostics and follow-up. This study aimed to explore auditory cortical maturation and language development, and the usability of an objective electroencephalogram-based biomarker in children with multiple disabilities. In 65 hearing aid and cochlear implant users (36 females; 36 with multiple disabilities; 44.3 ± 18.5 months of age, mean ± SD), auditory processing was examined using the P1 cortical auditory evoked response biomarker, and language development with the Preschool Language Scales 5th edition (PLS-5). During the study, all of the children received intensive extra language therapy for six months. No significant differences were found between the groups in P1 latency development, the proportion of abnormal P1 latencies, or the number of children whose P1 latencies changed from abnormal to normal during the study. The PLS-5 total language scores, auditory comprehension scores, or expressive communication scores did not differ between groups either. The P1 latencies showed meaningful negative correlations with the language scores. The results suggest that auditory cortex development is similar in hearing-impaired children with/without additional disabilities, and the P1 biomarker is a feasible tool to evaluate central auditory maturation in children with multiple disabilities. Full article

Prematurity is one of the most crucial risk factors negatively affecting the maturation of the auditory system. Children born preterm demonstrate high rates of hearing impairments. Auditory processing difficulties in preterm children might be a result of disturbances in the central auditory system development and/or sensory deprivation due to peripheral hearing loss. To investigate auditory processing in preterm children, we utilized a set of psychoacoustic tests to assess temporal processing and speech intelligibility. A total of 241 children aged 6–11 years old (136 born preterm and 105 healthy full-term children forming the control group) were assessed. The preterm children were divided into three groups based on their peripheral hearing status: 74 normal hearing (NH group); 30 children with bilateral permanent sensorineural hearing loss (SNHL group) and 32 children with bilateral auditory neuropathy spectrum disorder (ANSD group). The results showed significantly worse performance in all tests in premature children compared with full-term children. NH and SNHL groups showed significant age-related improvement in speech recognition thresholds in noise that might signify a “bottom-up” auditory processing maturation effect. Overall, all premature children had signs of auditory processing disorders of varying degrees. Analyzing and understanding the auditory processing specificity in preterm children can positively contribute to the more effective implementation of rehabilitation programs. Full article

Nutritional disturbances during the early postnatal period can have long-lasting effects on neurodevelopment and may be related to behavioural changes at adulthood. While such neuronal connection disruption can contribute to social and behaviour alterations, the dysregulation of the neuroendocrine pathways involved in nutrient-sensing balance may also cause such impairments, although the underlying mechanisms are still unclear. We aimed to evaluate sex-specific neurodevelopmental and behavioural changes upon postnatal overfeeding and determine the potential underpinning mechanisms at the central nervous system level, with a focus on the interconnection between synaptic and neuroendocrine molecular alterations. At postnatal day 3 (PND3) litters were culled to three animals (small litter procedure). Neurodevelopmental tests were conducted at infancy, whereas behavioural tests to assess locomotion, anxiety, and memory were performed at adolescence, together with molecular analysis of the hippocampus, hypothalamus, and prefrontal cortex. At infancy, females presented impaired acquisition of an auditory response, eye opening, olfactory discrimination, and vestibular system development, suggesting that female offspring neurodevelopment/maturation was deeply affected. Male offspring presented a transitory delay in locomotor performance., while both offspring had lower upper limb strength. At adolescence, both sexes presented anxious-like behaviour without alterations in short-term memory retention. Both males and females presented lower NPY1R levels in a region-specific manner. Furthermore, both sexes presented synaptic changes in the hippocampus (lower GABA_A in females and higher GABA_A levels in males), while, in the prefrontal cortex, similar higher GABA_A receptor levels were observed. At the hypothalamus, females presented synaptic changes, namely higher vGLUT1 and PSD95 levels. Thus, we demonstrate that postnatal overfeeding modulates offspring behaviour and dysregulates nutrient-sensing mechanisms such as NPY and GABA in a sex- and brain-region-specific manner. Full article

The maturation of the uncrossed medial olivocochlear (UMOC) efferent remains poorly documented to date. The UMOC efferent system allows listeners to not only detect but also to process, recognize, and discriminate auditory stimuli. Its fibers can be explored non-invasively by recording the effect of contralateral acoustic stimulation (CAS), resulting in a decrease in the amplitude of transient evoked otoacoustic emissions (TEOAE). The objective of the present cross-sectional study was to investigate how the effectiveness of this system varies with age in healthy subjects aged 8 years to adulthood. For this purpose, 120 right-handed native French-speaking subjects (57 females and 63 males) were divided into five age groups of 24 subjects each: 8y–10y, 10y–11y6m, 11y6m–13y, 13y–17y, and ≥18y. TEOAE amplitudes with and without CAS were recorded. The equivalent attenuation (EA) was calculated, corresponding to the change in TEOAE amplitude equivalent to the effect generated by CAS. General linear models were performed to control for the effect of ear, sex, and age on EA. No sex effect was found. A stronger EA was consistently found regardless of age group in the right ear compared to the left. In contrast to the right ear, for which, on average, EA remained constant across age groups, an increasingly weaker TEOAE suppression effect with age was found in the left ear, reinforcing the asymmetrical functioning of the UMOC efferent system in favor of the right ear in adulthood. Further studies are needed to investigate the lateralization of the UMOC efferent system and its changes over time in cases of atypical or reversed cortical asymmetries, especially in subjects with specific learning disorders. Full article

Parathyroid Hormone (PTH) plays a crucial role in the maintenance of calcium homeostasis directly acting on bone and kidneys and indirectly on the intestine. However, a large family of PTH-related peptides exists that exerts other physiological effects on different tissues and organs, such as the Central Nervous System (CNS). In humans, PTH-related peptides are Parathyroid Hormone (PTH), PTH-like hormones (PTHrP and PTHLH), and tuberoinfundibular peptide of 39 (TIP39 or PTH2). With different affinities, these ligands can bind parathyroid receptor type 1 (PTH1R) and type 2 (PTH2R), which are part of the type II G-protein-coupled-receptors (GPCRs) family. The PTH/PTHrP/PTH1R system has been found to be expressed in many areas of the brain (hippocampus, amygdala, hypothalamus, caudate nucleus, corpus callosum, subthalamic nucleus, thalamus, substantia nigra, cerebellum), and literature data suggest the system exercises a protective action against neuroinflammation and neurodegeneration, with positive effects on memory and hyperalgesia. TIP39 is a small peptide belonging to the PTH-related family with a high affinity for PTH2R in the CNS. The TIP39/PTH2R system has been proposed to mediate many regulatory and functional roles in the brain and to modulate auditory, nociceptive, and sexual maturation functions. This review aims to summarize the knowledge of PTH-related peptides distribution and functions in the CNS and to highlight the gaps that still need to be filled. Full article