Auditory brainstem response to paired clicks as a candidate marker of cochlear synaptopathy in humans.

OBJECTIVE: This study aimed to evaluate whether auditory brainstem response (ABR) using a paired-click stimulation paradigm could serve as a tool for detecting cochlear synaptopathy (CS). METHODS: The ABRs to single-clicks and paired-clicks with various inter-click intervals (ICIs) and scores for word intelligibility in degraded listening conditions were obtained from 57 adults with normal hearing. The wave I peak amplitude and root mean square values for the post-wave I response within a range delayed from the wave I peak (referred to as the RMSpost-w1) were calculated for the single- and second-click responses. RESULTS: The wave I peak amplitudes did not correlate with age except for the second-click responses at an ICI of 7 ms, and the word intelligibility scores. However, we found that the RMSpost-w1 values for the second-click responses significantly decreased with increasing age. Moreover, the RMSpost-w1 values for the second-click responses at an ICI of 5 ms correlated significantly with the scores for word intelligibility in degraded listening conditions. CONCLUSIONS: The magnitude of the post-wave I response for the second-click response could serve as a tool for detecting CS in humans. SIGNIFICANCE: Our findings shed new light on the analytical methods of ABR for quantifying CS.

Safety and Technical Efficacy of Pediatric Brainstem Biopsies: An Updated Meta-Analysis of 1000+ Children.

BACKGROUND: Brainstem tumors represent ∼10% of pediatric brain tumors, ∼80% of these are diffuse midline glioma (DMG). Given invariably poor prognosis in DMG, there continues to be immense variation worldwide in performing biopsy of these lesions. Several contemporary studies in recent years have provided new data to elucidate the safety profile of biopsy and an updated meta-analysis is thus indicated. METHODS: We found 29 studies of pediatric brainstem biopsy in the last 20 years (2003-2023, 1002 children). We applied meta-analysis of proportions using a random-effects model to generate point estimates, confidence intervals, and measures of heterogeneity. RESULTS: 87% of procedures were stereotactic needle biopsies (of these, 62% with a frame, 14% without frame, and 24% robotic.) Biopsy resulted in a histological diagnosis ("technical yield") in 96.8% of cases (95% CI 95.4-98.2). Temporary complications were seen in 6% (95 CI 4-8), with the most common neurological complications being 1) cranial nerve dysfunction, 2) worsening or new ataxia, and 3) limb weakness. Permanent complications (excluding death) were seen in 1% (95% CI 0.5-2), most commonly including cranial nerve dysfunction and limb weakness. 5 deaths were reported in the entire pooled cohort of 1002 children (0.5%). CONCLUSIONS: When counseling families on the merits of brainstem biopsy in children, it is reasonable to state that permanent morbidity is rare (<2%). If biopsy is performed specifically to facilitate enrollment in clinical trials requiring a molecular diagnosis, the risks of biopsy outlined here should be weighed against potential benefits of trial enrollment.

Prospective Evaluation of a Modified Apnea Test in Brain Death Candidates that Does Not Require Disconnection from the Ventilator.

BACKGROUND: The apnea test (AT) is an important component in the determination of brain death/death by neurologic criteria (BD/DNC) and often entails disconnecting the patient from the ventilator followed by tracheal oxygen insufflation to ensure adequate oxygenation. To rate the test as positive, most international guidelines state that a lack of spontaneous breathing must be demonstrated when the arterial partial pressure of carbon dioxide (PaCO2) ≥ 60 mm Hg. However, the loss of positive end-expiratory pressure that is associated with disconnection from the ventilator may cause rapid desaturation. This, in turn, can lead to cardiopulmonary instability (especially in patients with pulmonary impairment and diseases such as acute respiratory distress syndrome), putting patients at increased risk. Therefore, this prospective study aimed to investigate whether a modified version of the AT (mAT), in which the patient remains connected to the ventilator, is a safer yet still valid alternative. METHODS: The mAT was performed in all 140 BD/DNC candidates registered between January 2019 and December 2022: after 10 min of preoxygenation, (1) positive end-expiratory pressure was increased by 2 mbar (1.5 mm Hg), (2) ventilation mode was switched to continuous positive airway pressure, and (3) apnea back-up mode was turned off (flow trigger 10 L/min). The mAT was considered positive when spontaneous breathing did not occur upon PaCO2 increase to ≥ 60 mm Hg (baseline 35-45 mm Hg). Clinical complications during/after mAT were documented. RESULTS: The mAT was possible in 139/140 patients and had a median duration of 15 min (interquartile range 13-19 min). Severe complications were not evident. In 51 patients, the post-mAT arterial partial pressure of oxygen (PaO2) was lower than the pre-mAT PaO2, whereas it was the same or higher in 88 cases. In patients with pulmonary impairment, apneic oxygenation during the mAT improved PaO2. In 123 cases, there was a transient drop in blood pressure at the end of or after the mAT, whereas in 12 cases, the mean arterial pressure dropped below 60 mm Hg. CONCLUSIONS: The mAT is a safe and protective means of identifying patients who no longer have an intact central respiratory drive, which is a critical factor in the diagnosis of BD/DNC. Clinical trial registration DRKS, DRKS00017803, retrospectively registered 23.11.2020, https://drks.de/search/de/trial/DRKS00017803.

Hypertrophic olivary degeneration secondary to a Guillain Mollaret triangle cavernoma: Two case report.

Hypertrophic olivary degeneration (HOD) is a rare form of transsynaptic degeneration. It is caused by a damage at the Guillain-Mollaret triangle (GMT), which is defined by three anatomical structures: the dentate nucleus, the red nucleus, and the inferior olivary nucleus (ION). Clinically, it may be revealed by palatal myoclonus. On MRI, it appears as a unilateral or bilateral enlargement of the inferior olivary nucleus which shows a high signal intensity on T2-weighted images, with sometimes a cerebellar atrophy. Here we report 2 cases of healthy patients which present hemorrhagic brainstem cavernomas, complicated later by the development of palatal myoclonus and cerebellar ataxia, with MRI features corresponding to an (HOD) secondary to a (GMT) cavernoma. The purpose is to explain the mechanism of (HOD) subsequent to lesion in (GMT), and to describe magnetic resonance imaging features.

Neuronal network controlling REM sleep.

Rapid eye movement sleep is a state characterized by concomitant occurrence of rapid eye movements, electroencephalographic activation and muscle atonia. In this review, we provide up to date knowledge on the neuronal network controlling its onset and maintenance. It is now accepted that muscle atonia during rapid eye movement sleep is due to activation of glutamatergic neurons localized in the pontine sublaterodorsal tegmental nucleus. These neurons directly project and excite glycinergic/γ-aminobutyric acid-ergic pre-motoneurons localized in the ventromedial medulla. The sublaterodorsal tegmental nucleus rapid eye movement-on neurons are inactivated during wakefulness and non-rapid eye movement by rapid eye movement-off γ-aminobutyric acid-ergic neurons localized in the ventrolateral periaqueductal grey and the adjacent dorsal deep mesencephalic reticular nucleus. Melanin-concentrating hormone and γ-aminobutyric acid-ergic rapid eye movement sleep-on neurons localized in the lateral hypothalamus would inhibit these rapid eye movement sleep-off neurons initiating the state. Finally, the activation of a few limbic cortical structures during rapid eye movement sleep by the claustrum and the supramammillary nucleus as well as that of the basolateral amygdala would be involved in the function(s) of rapid eye movement sleep. In summary, rapid eye movement sleep is generated by a brainstem generator controlled by forebrain structures involved in autonomic control.

[Brainstem auditory evoked responses in horses with hearing loss and during general anesthesia]. / Hör- und Hirnstammfunktionsprüfung beim Pferd: Resultate bei ausgewählten klinischen Szenarien.

INTRODUCTION: The brainstem auditory evoked response (BAER) is a diagnostic approach to examine the hearing system of horses objectively. The aim of this BAER examination was the diagnosis of conductive or sensorineural hearing loss or deafness in horses with external otitis, head trauma, headshaking, tinnitus or skittish horses with eye disease. Brainstem dysfunction is induced by intracranial hypotension. BAER was used in horses with colic surgery which had a low arterial blood pressure during general anesthesia. The endoscopic finding of the guttural pouch was the ipsilateral mild to severe hypertrophy of the tympanostylohyoideum in horses with external otitis or head trauma. The otoscopic examination of standing sedated horses was done before BAER. The cartilagineous and osseous part of the external ear canal in horses with external otitis were obstructed with exsudate and tympanic membranes were not visible. Horses with right sided external otitis: right moderate to severe conductive hearing loss (significantly prolonged latencies of I, III, V and interpeak latencies I-III, I-V, III-V; thresholds of hearing levels 60 to 80 dB right); horses with left sided external otitis: left severe conductive hearing loss (no correct identification of BAER peaks, latencies not measurable, 80 dB); horse with left sided head trauma: severe left sided conductive hearing loss (blood in the left external ear canal, no visible tympanic membrane, no correct identification of BAER peaks, latencies not measurable, 80 dB); horses with head shaking: mild sensorineural hearing loss on both sides (on both sides osseous parts II/III with keratin scales of the junction, visible tympanic membranes, significantly prolonged V, I-III, I-V, 40 dB); moderate to severe skittish horses with chronic eye disease (mostly left sided equine recurrent uveitis): moderate sensorineural hearing loss on both sides (normal otoscopical findings, significantly prolonged latencies and interpeak latencies left; I-V, III-V right, 60 dB, pathological involvement in the auditory pathway of the brainstem between the cochlear nucleus and colliculus caudalis); horse with a tinnitus on both sides: mild sensorineural hearing loss on both sides (normal otoscopical findings, prolonged V, I-III, I-V, III-V, 40 dB, pathology of auditory nerve, cochlear nucleus and above the level of this nucleus); American paint horses: sensorineurale deafness on both sides (normal otoscopical findings, absent BAER peaks, isoelectric lines and 80 dB on both sides). The prolonged latencies of I, III and V including interpeak latencies I-III only left and I-V and III-V on both sides in horses with laparotomy during general anesthesia were associated with low arterial blood pressure (62 mmHg, median). These findings could demonstrate a hypotension in the brainstem too. The BAER could be a technical tool during general anesthesia for normalizing the arterial blood pressure and brainstem function to prevent imbalance of body movements after general anesthesia.

INTRODUCTION: L'examen objectif de l'audition chez le cheval est réalisé par la mesure des Potentiels Évoqués Auditifs (PEA) ou Brainstem Auditory-Evoked Response (BAER). L'objectif de ces examens est de diagnostiquer une surdité de transmission ou neurosensorielle ou une surdité chez les chevaux souffrant d'otite externe, de traumatisme crânien, de headshaking, d'acouphènes ou chez des chevaux craintifs souffrant d'une maladie oculaire. Étant donné que l'audiométrie du tronc cérébral vérifie également la fonction du tronc cérébral, des chevaux ayant subi une laparotomie et une déshydratation préopératoire ont été examinés pour détecter un dysfonctionnement du tronc cérébral dû à une baisse de la pression artérielle. L'otoscopie et l'audiométrie du tronc cérébral (système AEP Corona) ont été réalisées. Les résultats de l'otoscopie chez les chevaux atteints d'otite externe: Pars cartilaginea et ossea degré III, tympan non visible. Les résultats de l'endoscopie des poches gutturales chez les chevaux atteints d'otite externe exsudative ou de traumatisme crânien: toujours une augmentation ou une hypertrophie ipsilatérale du tympanostylohyoïdien. Les résultats de la BAER des chevaux atteints d' une otite externe à droite sont les suivants: surdité de transmission moyenne à sévère à droite (ondes I, III, V significativement prolongées, latences interpicales I-III, I-V, III-V par rapport au groupe de contrôle, valeurs limites au-dessus du seuil auditif normal 60 à 80 dB); chevaux atteints d'otite externe à gauche: surdité de transmission de haut niveau à gauche (ondes non identifiables, 80 dB à gauche); chevaux avec une fistule auriculaire à droite: surdité de perception bilatérale de bas niveau (allongement significatif des ondes III, V et des latences interpicales des deux côtés, 40 dB); cheval avec traumatisme crânien à gauche: surdité de transmission de degré élevé (à gauche, sang dans le conduit auditif externe, tympan non visible, ondes non identifiables, 80 dB); chevaux avec headshaking: surdité de perception de degré faible (des deux côtés, pars ossea de degré II, tympans visibles, allongement significatif V, I-III, I-V, 40 dB); chevaux présentant une peur et une maladie oculaire: surdité moyenne, neurosensorielle (otoscopie normale, allongement significatif de toutes les ondes et des latences interpeak à gauche, I-V, III-V à droite, 60 dB, vitesse pathologique de conduction des voies auditives dans le tronc cérébral); American Paint Horses: surdité neurosensorielle (otoscopie normale, ligne isoélectrique bilatérale des HA, 80 dB). Les ondes I, III et V prolongées et les latences interpicales I-III, I-V et III-V chez les chevaux ayant subi une laparotomie sont associées à la baisse de la pression artérielle (62 mmHg, médiane) pendant l'anesthésie générale et indiquent une hypotension dans le tronc cérébral. Pendant l'anesthésie générale, l'audiométrie du tronc cérébral offre une possibilité particulière de détecter le dysfonctionnement du tronc cérébral, de réguler la pression artérielle et de garantir un lever sans problème avec un équilibre auditif et visuel de la posture après l'anesthésie générale.

A ventral brainstem neurenteric cyst - A case report and review of the pre-brainstem location.

Background: Neurenteric cysts are uncommon, benign endoderm-derived lesions that result from aberrant embryologic development of the notochord. They are typically located in the intradural extramedullary spinal cord and rarely located intracranially. Contrary to spinal-located cysts, intracranial cysts are rarer in the pediatric population. Clinically, they may present with symptoms of mass effect, or they can be incidentally discovered. Case Description: A 10-year-old healthy female child presented with recurrent headaches. The physical and neurological examination was unremarkable. Brain magnetic resonance imaging (MRI) showed a well-demarcated lesion anterior to the pontomedullary junction with striking T1 and T2/T2 fluid-attenuated inversion recovery high-signal intensity and a small rounded nodule within of low signal on T1, T2, and T2*. On initial conservative strategy with serial brain MRI, there was a progressive enlargement of the lesion with significant mass effect on the brainstem. The patient underwent a right retrosigmoid craniotomy, and the cyst wall was fenestrated and drained. Part of the cyst wall and the solid nodule were adherent to the brainstem and basilar artery and were not removed. The histologic findings were consistent with the diagnosis of a benign endodermal cyst. The postoperative period was uneventful. Conclusion: We report a successful surgical treatment of this rare congenital cyst located in the ventral brainstem. We present pre-and post-operative imaging findings, intraoperative microscopic images of the procedure, and a brief review of relevant clinical literature on the topic.

New Step in Understanding the Pathogenetic Mechanism of Sudden Infant Death Syndrome: Involvement of the Pontine Reticular Gigantocellular Nucleus.

This study aimed to investigate, for the first time, the potential role of the gigantocellular nucleus, a component of the reticular formation, in the pathogenetic mechanism of Sudden Infant Death Syndrome (SIDS), an event frequently ascribed to failure to arouse from sleep. This research was motivated by previous experimental studies demonstrating the gigantocellular nucleus involvement in regulating the sleep-wake cycle. We analyzed the brains of 48 infants who died suddenly within the first 7 months of life, including 28 SIDS cases and 20 controls. All brains underwent a thorough histological and immunohistochemical examination, focusing specifically on the gigantocellular nucleus. This examination aimed to characterize its developmental cytoarchitecture and tyrosine hydroxylase expression, with particular attention to potential associations with SIDS risk factors. In 68% of SIDS cases, but never in controls, we observed hypoplasia of the pontine portion of the gigantocellular nucleus. Alterations in the catecholaminergic system were present in 61% of SIDS cases but only in 10% of controls. A strong correlation was observed between these findings and maternal smoking in SIDS cases when compared with controls. In conclusion we believe that this study sheds new light on the pathogenetic processes underlying SIDS, particularly in cases associated with maternal smoking during pregnancy.

A non-enhancing, T2 fluid-attenuated inversion recovery hyperintense, diffusion-restricting brainstem lesion in an EGFR tyrosine kinase inhibitor-treated non-small-cell lung cancer patient.

Leptomeningeal metastasis (LM) is a devastating complication of malignancy. Diagnosis relies on both contrast enhancement on imaging and malignant cells in cerebral spinal fluid cytology. Though early detection and prompt intervention improves survival, the detection of LM is limited by false negatives. A rare brainstem imaging finding uncovered specifically in EGFR mutation-positive lung cancer patients may represent an early sign of LM. This sign demonstrates high signal on T2 fluid-attenuated inversion recovery and diffusion-weighted imaging sequences, but paradoxically lacks correlative contrast enhancement. Here we report a case of a 72-year-old female EGFR-positive lung cancer patient who developed this lesion following treatment with two first-generation EGFR tyrosine kinase inhibitors then showed subsequent response to osimertinib, an irreversible third-generation EGFR tyrosine kinase inhibitor.

A non-enhancing, T2 FLAIR hyperintense, diffusion-restricting brainstem lesion in an EGFR-positive lung cancer patient may represent an early indicator of leptomeningeal metastases.

NMDAR dysfunction and the regulation of dopaminergic transmission in schizophrenia.

A substantial body of evidence implicates dysfunction in N-methyl-d-aspartate receptors (NMDARs) in the pathophysiology of schizophrenia. This article illustrates how NMDAR dysfunction may give rise to many of the neurobiological phenomena frequently associated with schizophrenia with a particular focus on how NMDAR dysfunction affects the thalamic reticular nucleus (nRT) and pedunculopontine tegmental nucleus (PPTg). Furthermore, this article presents a model for schizophrenia illustrating how dysfunction in the nRT may interrupt prefrontal regulation of midbrain dopaminergic neurons, and how dysfunction in the PPTg may drive increased, irregular burst firing.

Hearing Assessment of Free-Ranging Owls and Implications for Wildlife Rehabilitation: 31 Cases (2014-2023).

Owls, members of the avian order Strigiformes, are nocturnal birds of prey that are found worldwide except for Antarctica. Traumatized, free-ranging owls are commonly presented to veterinary hospitals and wildlife rehabilitation facilities with the goal of providing medical care and rehabilitation to enable release back into their natural habitat. Minimal guidelines exist for the release of wildlife, and whereas a need for functional vision is described in raptors, assessing and evaluating hearing is usually not mentioned. This can be problematic for nocturnal predators because hearing is the primary sense utilized by owls when hunting and navigating in their dark environment. The brainstem auditory evoked response (BAER) test is a minimally invasive, objective assessment of hearing commonly used in companion animals. To the authors' knowledge, routine or standardized BAER evaluation has not been reported in traumatized, free-ranging owls. In the following retrospective study, 31 free-ranging owls presented to the University of Georgia Veterinary Teaching Hospital for known or suspected trauma or being found in a debilitated state underwent BAER testing to assess for the presence of complete sensorineural hearing loss. Similar to assessment of hearing in companion animals, the BAER test was elicited using a broad click stimulus delivered at 85 dB nHL. In all owls, qualitative assessment and peak latency measurements of the BAER test reflected hearing ability. This study highlights the importance of hearing in nocturnal raptors, how BAER testing can aid in decision making regarding rehabilitation, and provides a foundation for further investigation of hearing loss in traumatized owls. We suggest that veterinarians working with free-ranging owls in a rehabilitation setting should consider BAER testing as part of routine diagnostic testing.

A novel copy number variant in the murine Cdh23 gene gives rise to profound deafness and vestibular dysfunction.

Hearing loss is the most common congenital sensory deficit worldwide and exhibits high genetic heterogeneity, making molecular diagnoses elusive for most individuals. Detecting novel mutations that contribute to hearing loss is crucial to providing accurate personalized diagnoses, tailored interventions, and improving prognosis. Copy number variants (CNVs) are structural mutations that are understudied, potential contributors to hearing loss. Here, we present the Abnormal Wobbly Gait (AWG) mouse, the first documented mutant exhibiting waltzer-like locomotor dysfunction, hyperactivity, circling behaviour, and profound deafness caused by a spontaneous CNV deletion in cadherin 23 (Cdh23). We were unable to identify the causative mutation through a conventional whole-genome sequencing (WGS) and variant detection pipeline, but instead found a linked variant in hexokinase 1 (Hk1) that was insufficient to recapitulate the AWG phenotype when introduced into C57BL/6J mice using CRISPR-Cas9. Investigating nearby deafness-associated genes revealed a pronounced downregulation of Cdh23 mRNA and a complete absence of full-length CDH23 protein, which is critical for the development and maintenance of inner ear hair cells, in whole head extracts from AWG neonates. Manual inspection of WGS read depth plots of the Cdh23 locus revealed a putative 10.4 kb genomic deletion of exons 11 and 12 that was validated by PCR and Sanger sequencing. This study underscores the imperative to refine variant detection strategies to permit identification of pathogenic CNVs easily missed by conventional variant calling to enhance diagnostic precision and ultimately improve clinical outcomes for individuals with genetically heterogenous disorders such as hearing loss.

Postoperative brainstem cavernous malformations complicated with LGI1 encephalitis and hypertrophic olivary degeneration: A case report and literature review.

We presented a case of a 34-year-old male with postoperative brainstem cavernous malformations complicated with LGI1 encephalitis and secondary hypertrophic olivary degeneration (HOD). Due to recurrent dizziness and headache, the patient was diagnosed as brainstem cavernous malformations with recurrent hemorrhage and underwent resection. He subsequently developed unexplained abnormal mental behavior 1 month after the surgery, and diagnosed with LGI1 encephalitis. Six months later, cranial MRI showed HOD. This condition is rare in clinical practice,and a complex mechanism underlies the occurrence.

Ion channel dysregulation and cellular adaptations to alpha-synuclein in stressful pacemakers of the parkinsonian brainstem.

Parkinson's disease (PD) is diagnosed by its cardinal motor symptoms that are associated with the loss of dopamine neurons in the substantia nigra pars compacta (SNc). However, PD patients suffer from various non-motor symptoms years before diagnosis. These prodromal symptoms are thought to be associated with the appearance of Lewy body pathologies (LBP) in brainstem regions such as the dorsal motor nucleus of the vagus (DMV), the locus coeruleus (LC) and others. The neurons in these regions that are vulnerable to LBP are all slow autonomous pacemaker neurons that exhibit elevated oxidative stress due to their perpetual influx of Ca2+ ions. Aggregation of toxic α-Synuclein (aSyn) - the main constituent of LBP - during the long prodromal period challenges these vulnerable neurons, presumably altering their biophysics and physiology. In contrast to pathophysiology of late stage parkinsonism which is well-documented, little is known about the pathophysiology of the brainstem during prodromal PD. In this review, we discuss ion channel dysregulation associated with aSyn aggregation in brainstem pacemaker neurons and their cellular responses to them. While toxic aSyn elevates oxidative stress in SNc and LC pacemaker neurons and exacerbates their phenotype, DMV neurons mount an adaptive response that mitigates the oxidative stress. Ion channel dysregulation and cellular adaptations may be the drivers of the prodromal symptoms of PD. For example, selective targeting of toxic aSyn to DMV pacemakers, elevates the surface density of K+ channels, which slows their firing rate, resulting in reduced parasympathetic tone to the gastrointestinal tract, which resembles the prodromal PD symptoms of dysphagia and constipation. The divergent responses of SNc & LC vs. DMV pacemaker neurons may explain why the latter outlive the former despite presenting LBPs earlier. Elucidation the brainstem pathophysiology of prodromal PD could pave the way for physiological biomarkers, earlier diagnosis and novel neuroprotective therapies for PD.

Association of connexin36 with adherens junctions at mixed synapses and distinguishing electrophysiological features of those at mossy fiber terminals in rat ventral hippocampus.

BACKGROUND: Granule cells in the hippocampus project axons to hippocampal CA3 pyramidal cells where they form large mossy fiber terminals. We have reported that these terminals contain the gap junction protein connexin36 (Cx36) specifically in the stratum lucidum of rat ventral hippocampus, thus creating morphologically mixed synapses that have the potential for dual chemical/electrical transmission. METHODOLOGY: Here, we used various approaches to characterize molecular and electrophysiological relationships between the Cx36-containing gap junctions at mossy fiber terminals and their postsynaptic elements and to examine molecular relationships at mixed synapses in the brainstem. RESULTS: In rat and human ventral hippocampus, many of these terminals, identified by their selective expression of vesicular zinc transporter-3 (ZnT3), displayed multiple, immunofluorescent Cx36-puncta representing gap junctions, which were absent at mossy fiber terminals in the dorsal hippocampus. In rat, these were found in close proximity to the protein constituents of adherens junctions (i.e., N-cadherin and nectin-1) that are structural hallmarks of mossy fiber terminals, linking these terminals to the dendritic shafts of CA3 pyramidal cells, thus indicating the loci of gap junctions at these contacts. Cx36-puncta were also associated with adherens junctions at mixed synapses in the brainstem, supporting emerging views of the structural organization of the adherens junction-neuronal gap junction complex. Electrophysiologically induced long-term potentiation (LTP) of field responses evoked by mossy fiber stimulation was greater in the ventral than dorsal hippocampus. CONCLUSIONS: The electrical component of transmission at mossy fiber terminals may contribute to enhanced LTP responses in the ventral hippocampus.

Rethinking the Accessibility of Hearing Assessments for Children with Developmental Disabilities.

We aim to determine the accessibility of gold-standard hearing assessments - audiogram or auditory brainstem response (ABR) - during the first 3 months of hearing health care for children with and without developmental disabilities. Electronic health records were examined from children (0-18 years) who received hearing health care at three hospitals. Children with developmental disabilities had a diagnosis of autism, cerebral palsy, Down syndrome, or intellectual disability. Assessments from the first 3 months were reviewed to determine if ≥ 1 audiogram or ABR threshold was recorded. To evaluate differences in assessment based on disability status, logistic regression models were built while accounting for age, race, ethnicity, sex, and site. Of the 131,783 children, 9.8% had developmental disabilities. Whereas 9.3% of children in the comparison group did not access a gold-standard assessment, this rate was 24.4% for children with developmental disabilities (relative risk (RR) = 3.79; p < 0.001). All subgroups were at higher risk relative to the comparison group (all p < 0.001): multiple diagnoses (RR = 13.24), intellectual disabilities (RR = 11.52), cerebral palsy (RR = 9.87), Down syndrome (RR = 6.14), and autism (RR = 2.88). Children with developmental disabilities are at high risk for suboptimal hearing evaluations that lack a gold-standard assessment. Failure to access a gold-standard assessment results in children being at risk for late or missed diagnosis for reduced hearing. Results highlight the need for (1) close monitoring of hearing by healthcare providers, and (2) advancements in testing methods and guidelines.

The spectrum of anti-GQ1B antibody syndrome: beyond Miller Fisher syndrome and Bickerstaff brainstem encephalitis.

INTRODUCTION: Since the initial identification of Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE),significant milestones have been achieved in understanding these diseases.Discoveries of common serum antibodies (IgG anti-GQ1b), antecedent infections, neurophysiological data, andneuroimaging suggested a shared autoimmune pathogenetic mechanism rather than distinct pathogenesis, leadingto the hypothesis that both diseases are part of a unified syndrome, termed "Fisher-Bickerstaff syndrome". The subsequent identification of atypical anti-GQ1b-positive forms expanded the classification to a broader condition known as "Anti-GQ1b-Antibody syndrome". METHODS: An exhaustive literature review was conducted, analyzing a substantial body of research spanning from the initialdescriptions of the syndrome's components to recent developments in diagnostic classification and researchperspectives. RESULTS: Anti-GQ1b syndrome encompasses a continuous spectrum of conditions defined by a common serological profilewith varying degrees of peripheral (PNS) and central nervous system (CNS) involvement. MFS and BBE represent theopposite ends of this spectrum, with MFS primarily affecting the PNS and BBE predominantly involving the CNS.Recently identified atypical forms, such as acute ophthalmoparesis, acute ataxic neuropathy withoutophthalmoparesis, Guillain-Barré syndrome (GBS) with ophthalmoparesis, MFS-GBS and BBE-GBS overlap syndromes,have broadened this spectrum. CONCLUSION: This work aims to provide an extensive, detailed, and updated overview of all aspects of the anti-GQ1b syndromewith the intention of serving as a stepping stone for further shaping thereof. Special attention was given to therecently identified atypical forms, underscoring their significance in redefining the boundaries of the syndrome.

A phase 2a study investigating the effects of ritlecitinib on brainstem auditory evoked potentials and intraepidermal nerve fiber histology in adults with alopecia areata.

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9-month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50-mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double-blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4-week loading dose of 200 mg QD or placebo for 9 months (placebo-controlled phase); they then entered the active-therapy extension and received ritlecitinib 50 mg QD (with a 4-week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I-V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans.

Neuromyelitis optica spectrum disorder with acute brainstem manifestations as initial symptoms.

Objective: To explore the clinical features and prognosis of patients with neuromyelitis optica spectrum disorder (NMOSD) initially presenting with acute brainstem symptoms. Methods: The clinical data of NMOSD patients admitted to two medical centers were collected. The clinical characteristics, laboratory data, neuroimaging features and prognoses of patients with NMOSD with acute brainstem manifestations as initial symptoms (NMOSD-BSMIS) were analyzed. The clinical features and prognosis of patients with NMOSD-BSMIS and patients with NMOSD with other manifestations as initial symptoms (NMOSD-OMIS) were compared. Results: Fifty-two patients (18.37 %, 52/283) initially presented with acute brainstem symptoms. Intractable nausea, vomiting or hiccups, diplopia, vertigo, headache, and facial hypoesthesia were the initial symptoms in most of the patients. The percentage of patients who were positive for serum aquaporin 4 (AQP4)-IgG antibodies was 81.63 % (40/49). MRI revealed that the lesions were usually located in the postrema, dorsal medulla oblongata, pons and other areas around the fourth ventricle. The early-stage misdiagnosis rate was 46.15 %. Compared with those in the non-misdiagnosed group, the age of onset of patients in the NMOSD-BSMIS group was older, and the proportion of patients admitted to the neurology department as the first department was lower in the misdiagnosed group. The annual relapse rate of patients who underwent NMOSD-BSMIS was significantly greater than that of patients who underwent NMOSD-OMIS (P < 0.01). Conclusions: NMOSD patients can initially present with different brainstem symptoms. The early misdiagnosis rate of NMOSD-BSMIS is high. Moreover, if patients are older or initially admitted to nonneurological departments, they are more likely to be misdiagnosed. Moreover, the annual recurrence rate of NMOSD-BSMIS is greater in the early stage.

The breath shape controls intonation of mouse vocalizations.

Intonation in speech is the control of vocal pitch to layer expressive meaning to communication, like increasing pitch to indicate a question. Also, stereotyped patterns of pitch are used to create distinct sounds with different denotations, like in tonal languages and, perhaps, the 10 sounds in the murine lexicon. A basic tone is created by exhalation through a constricted laryngeal voice box, and it is thought that more complex utterances are produced solely by dynamic changes in laryngeal tension. But perhaps, the shifting pitch also results from altering the swiftness of exhalation. Consistent with the latter model, we describe that intonation in most vocalization types follows deviations in exhalation that appear to be generated by the re-activation of the cardinal breathing muscle for inspiration. We also show that the brainstem vocalization central pattern generator, the iRO, can create this breath pattern. Consequently, ectopic activation of the iRO not only induces phonation, but also the pitch patterns that compose most of the vocalizations in the murine lexicon. These results reveal a novel brainstem mechanism for intonation.