Although SARS-CoV-2, the virus that causes COVID-19 has been responsible for pneumonia, recent studies indicate that it also affects the kidneys, heart, and brain, among other vital organs. Evidence suggests that this virus may travel retrogradely from the olfactory epithelium to brain stem sections, causing neurological impairments in a significant number of individuals. Individuals with severe COVID-19 frequently have elevated cytokines that promote inflammation and acute respiratory failure and require frequent supportive ventilation. These factors are believed to contribute to cognitive deterioration. Severe neurological outcomes in COVID-19 patients include- paralysis, stroke, cranial nerve deficits, delirium, encephalopathy, seizures, and meningitis. The virus, with its unique structure, and a high binding affinity for the human enzyme ACE2 (used as an entry point by the virus), contributes significantly to its deadly nature. Furthermore, to address the outbreak effectively, researchers worldwide must develop precise treatment strategies. Advancing new diagnostic and treatment methods to mitigate the long-term effects of COVID-19 on cognition requires further epidemiological research and clinical experience. Additionally, by understanding the virus's impact on cognitive functions, healthcare professionals can develop targeted treatments to alleviate these severe neurological consequences.

The African spiny mouse (Acomys dimidiatus) is a unique mammalian model capable of scarless tissue regeneration, extending to the nervous system. Unlike conventional rodents, Acomys show significantly higher levels of adult brain stem cells, enhanced functional plasticity after brain injury, and the ability to regenerate and regain function following severe spinal cord damage. While the regenerative capacity of the Acomys central nervous system (CNS) is only beginning to be explored, existing studies have already challenged the long-standing dogma that adult mammals are incapable of CNS recovery after injury. This review provides a critical overview on the current knowledge of Acomys nervous system biology, from development to repair. We summarize the known cellular and mechanistic insights and highlight the current outstanding questions and research priorities. Understanding how Acomys achieves CNS functional recovery, an ability unmatched by any other known mammal, may ultimately guide strategies to enhance repair in nonregenerative mammals, including humans.

Cisplatin is used for treatment of various carcinomas in clinics but is associated with the adverse effects of nausea and vomiting. We investigated the antiemetic effect of gabapentsal; a gabapentinoid derivative against cisplatin (10mg/kg) induced vomiting in pigeons and the neurochemical mechanisms centrally and peripherally and the involvement of dopaminergic receptors. Established video recording setup was used for behavioral experiments while High Performance Liquid Chromatography system coupled with electrochemical detector (HPLC-ECD) was used for the quantification of neurotransmitters 5-hydroxytryptamine (5HT) and its metabolite; 5-hydroxy indole acetic acid (5-HIAA), dopamine (DA) and its metabolites; dihydroxy phenyl acetic acid (DOPAC), homovanillic acid (HVA) and noradrenaline (NA) centrally in brain stem while, peripherally in small intestine. Cisplatin (10mg/kg i.v.) induced emesis without lethality up to the observation period (3h.). Gabapentsal attenuated cisplatin induced emesis ~ 77.22%; the standard drug, gabapentin (GB; 100mg/kg), produced ~ 57.55% reduction. Gabapentsal suppressed (p < 0.05 - p < 0.01) the concentration of 5HT and 5-HIAA in the brain stem and intestine. In continuation, a decline (P < 0.05 - p < 0.01) in the concentration of DA and its metabolite DOPAC in the brain stem while DA concentration was decreased (p < 0.05) in the intestine only. The standard gabapentin (100mg/kg) decreased (p < 0.05) the concentration of 5HT and NA in the intestine only. Furthermore; gabapentsal attenuated (p < 0.001) quinpirole (3mg/kg) induced vomiting but no effect on neurotransmitters and their metabolites was noted. In conclusion, gabapentsal has antiemetic activity against cisplatin and quinpirole induced vomiting mediated by serotonergic and dopaminergic components centrally and peripherally.

Mechanism of esophageal peristalsis or sequential contractions of the skeletal and smooth muscle esophagus resides at multiple levels, i.e., brain stem (central pattern generator), neurons within the wall of the esophagus (myenteric plexus) and smooth muscle (myogenic). Esophageal peristalsis consists of initial inhibition followed by excitation, for which there may be parallel pathways from the central program generator, travelling via the vagus nerve to communicate with the inhibitory and excitatory neurons of the myenteric plexus. Primary and secondary esophageal peristalsis are associated with concurrent contraction and relaxation of the circular and longitudinal muscle layers. The longitudinal muscle contraction in the contracted segment exerts mechanical stretch on the segment ahead of it, which likely activate the mechanosensitive inhibitory motor neurons in the myenteric plexus to induce descending relaxation, a peripheral mechanism of the peristaltic reflex. In the achalasia esophagus, there is inflammation and fibrosis in the muscularis propria and myenteric plexus, resulting in loss of inhibitory nerves in the myenteric plexus. The above also results in replacement of muscle with fibrous tissue in the muscularis propria of the lower esophageal sphincter (LES), impaired LES relaxation and low distensibility of the esophagogastric junction in achalasia esophagus. The esophageal hiatus contains a pad of fat which is replaced with fibrosis in patients with achalasia esophagus. Whether hiatal fibrosis leads to impaired LES relaxation/low distensibility of the esophagogastric junction, and changes in esophageal peristalsis are secondary to obstruction requires further study. Esophageal hypersensitivity is currently the favored mechanism of "angina like" esophageal pain and refractory heartburn. Spastic or long-duration contractions of the longitudinal muscle of esophagus may also play a role in the genesis of non-cardiac esophageal pain and heartburn sensation.

Mitochondrial complex III deficiency nuclear type 2 (MC3DN2) is a rare inherited neurometabolic disease. A 34-year-old male had neuropsychiatric episodes, progressive cerebellar degeneration, myopathy, polyneuropathy, and brain stem and basal ganglion lesions since childhood. Muscle biopsy revealed mitochondrial abnormalities. Two novel TTC19 pathogenic variants were detected. To analyze phenotypic characteristics of MC3DN2 related to clinical onset age, neurological presentation and brain MRI regarding infantile and childhood-onset (ICO) and adolescent and adult-onset (AAO) disease in a cohort composed of our patient and the cases reported in the literature were compared. It revealed that, clinically, cerebellar ataxia was common in both groups, nystagmus was more frequently noted in AAO patients, and psychiatric disturbances were more common in ICO patients. Regarding MRI findings, basal ganglion lesions were more prevalent in ICO patients, and inferior olive lesions were more frequent in AAO patients. These conspicuous phenotypic features of MC3DN2 may suggest diagnosis of this distinctive disease. The differences in clinical features and brain lesions associated with clinical onset age could provide crucial insights into the phenotypic landscape of MC3DN2.

The role of DTL in maintaining survival of cochlear hair cell and hearing function.

Abstract Background A wide range of sedative drugs are used for auditory brain stem response testing in pediatric population, but still there is no ideal sedative drug, because no single agent can provide adequate sedation while minimizing serious risks such as cardiorespiratory depression and also allow for rapid recovery. Methods A randomized clinical trial on 113 children aged 3–6 years with normal hearing. Group (A) comprised 83 children with normal neurodevelopment, and Group (B) included 30 children with neurodevelopmental disorders (NDD). Each group was subdivided according to the sedative used, either melatonin or CH. All children underwent otological examination, full audiological assessment to ensure normal hearing thresholds. Then ABR was done with the appropriate preparations; sedation was received, vital signs and adverse effects were monitored. Results Group A, initial sedation success rate was 69.8% with melatonin and 87.5% with chloral hydrate, with no statistically significant difference. Supplemental melatonin dosing increased success to 81.4%. nearly the same pattern was found with the children with NDD. Vital signs remained within normal ranges for both drugs, although chloral hydrate caused slightly more reductions in heart and respiratory rates. Arousal time was significantly shorter with melatonin. Adverse effects were mild and less frequent with melatonin. ABR thresholds and most of the waveform parameters showed no clinically significant differences between both sedatives. Conclusion Melatonin is a safe and effective alternative to chloral hydrate for sedation during paediatric ABR testing. Its flexible dosing, rapid recovery, favorable safety profile, and minimal impact on ABR parameters support its use in routine clinical practice, particularly in difficult-to-test children.

Age and region dependent biomechanical and ultrastructural differences in porcine white matter.

Sphingosine-1-phosphate receptors (S1PRs) play an important regulatory role in various biological processes, including immune responses and neurodegeneration. We report the binding specificity of an S1PR1 PET radiotracer, [18F]TZ82112, via invitro autoradiography blocking studies with S1PR1 modulators in human and rat brain tissues and evaluate the tracer kinetics via kinetic modeling in nonhuman primates (NHPs) to assess its potential for clinical translation. A total of 12 scans were performed in four male macaques (M 1-4). Each macaque had 1-4 baseline scans and at least one blocking scan in three macaques. Arterial input function (AIF) was obtained from M2 and M3 under baseline conditions and M3 after pretreatment with cold TZ82112. The metabolite-corrected plasma AIF was applied to several kinetic models-one-tissue compartment (1TC) and 2TC, and Graphical Logan Analysis. Five candidate reference regions, namely the whole cerebellum, brain stem, occipital cortex, corpus callosum, and cerebral white matter, were investigated for deriving the standardized uptake value ratios (SUVr). The 2TC with four parameters (2TC4K) with blood volume (Vb) fitting is the most suitable kinetic model for evaluating [18F]TZ82112 kinetics. Pretreatment with unlabeled TZ82112 reduced uptake of [18F]TZ82112, demonstrating specific binding in all analyzed regions, including potential reference regions. Reduced tracer uptake in invitro blocking studies further confirmed the tracer specificity to S1PR1. We concluded that accurate [18F]TZ82112 quantification requires AIF measurements, owing to the lack of a suitable reference region; no reference region modeling approach or SUVr would be appropriate. Fast tracer uptake and high VT values, particularly in the prefrontal cortex and striatum, indicated that [18F]TZ82112 enters the brain quickly and has high S1PR1-specific binding in NHP brain. The current findings further support [18F]TZ82112 as a good PET radiotracer for the quantification of S1PR1 in the brain, provided an AIF is employed.

Individual differences in neural circuits underlying emotional regulation, motivation, and decision-making are implicated in many psychiatric illnesses. Interindividual variability in these circuits may manifest, at least in part, as individual differences in impulsivity. Impulsivity reflects a tendency towards rapid, unplanned reactions to internal or external stimuli without considering potential negative consequences, coupled with difficulty inhibiting responses. Here, we use multivariate machine learning approaches (brain-based predictive models) to explore the neural bases of impulsivity. We consider multiple impulsivity measures, neuroanatomical features (cortical thickness, surface area, and gray matter volume, as well as non-cortical gray matter volume), and sexes (females and males) in a large sample of youth from the Adolescent Brain Cognitive Development (ABCD) Study at baseline (n = 8630), two-year follow-up (n = 5998), four-year follow-up (n = 4844), and six-year follow-up (n = 3100). Using brain-based predictive models, we demonstrate that regional variations in cortical thickness, surface area, and gray matter volume significantly predict self-reported impulsivity measures, with associations varying across impulsivity dimensions and developmental timepoints. Impulsivity broadly maps onto default mode, limbic, ventral attention, and visual networks, as well as cerebellar and brain stem structures. While many relationships are stable across sexes and developmental time points, others exhibit sex effects and dynamic changes. These results suggest that neuroanatomy is linked to self-reported impulsivity in youth and highlight the complexity of these relationships across measures, features, sexes, and time points. This work also emphasizes the importance of adopting a multivariate and sex-specific approach in neuroimaging and behavioral research.

We have discovered a highly specialized innervation of the forebrain by pituitary adenylate cyclase-activating polypeptide (PACAP) immunohistochemistry originating from the brain stem that uses glutamate, acetylcholine, and PACAP, and other peptides as neurotransmitters. The parent neurons of the axons are in the Kölliker-Fuse nucleus, and their terminals form calyx-like multirelease-site synapses in the rodent forebrain extended amygdala similar to the calyx of Held in the auditory brain stem. The latter is a giant, excitatory, cup-like axo-somatic high-fidelity synapse. The PACAP-positive terminals also form enveloping axo-somatic specialization with mixed glutamatergic and cholinergic molecular identities, co-expressing vesicular glutamate transporter 1 (VGluT1), VGluT2, vesicular acetylcholine transport (VAChT), and the neuropeptides PACAP, calcitonin gene-related peptide, and neurotensin, together with calretinin in the presynaptic compartment. We identified a distinct neuronal subpopulation in the pontine Kölliker-Fuse region of the parabrachial complex that gives rise to these calyceal terminals, which engulf Protein kinase C delta (PKCδ+) / Glutamate delta receptor 1 (GluD1+) somata in the capsular central amygdala and oval bed nucleus of the stria terminalis. Strikingly, GluD1 immunolabeling is concentrated at axo-somatic contact zones apposed to VAChT+ presynaptic vesicle cluster zones but is absent from postsynaptic densities of conventional type I synapses within the same terminals. The results demonstrate a previously unrecognized multimodal calyx-like synapse in the forebrain, with parallel fast ionotropic and modulatory peptidergic neurotransmission mechanisms, which is a substrate for high-fidelity signal transmission within viscerosensory-emotional circuits.

Neural basis for mutant ATAXIN-1 induced respiratory dysfunction in mouse models of spinocerebellar ataxia type 1

Dyspnea has many possible causes and, like pain, is felt in different qualities. Afferent signals originate from the chemoreceptors (pH, O2 and CO2) as well as from mechanoreceptors in the lungs, respiratory muscles and thorax. Complexity arises from the fact that both blood gases and the acid-base balance have to be regulated. There is almost always a combination of afferent incoming signals, which can reinforce each other but also determine the quality of the dyspnea experienced. In humans, O2 is mainly measured peripherally, whereas CO2 and pH are measured centrally. The areas of the brain involved in regulation are largely located in the brain stem, but cortical areas are also involved in the perception of dyspnea.The majority of patients experience a feeling of air hunger as the main discomfort. Subsequently, this results in emotional processing with the components of anxiety, frustration and fear.

The autonomic nervous system (ANS) coordinates the body's response to stress. Proinflammatory cytokines [e.g., tumor necrosis factor-alpha (TNFα)], released in response to different stressors, may influence underlying pathophysiology involving autonomic dysfunction. The present study evaluated the impact of peripheral TNFα on cellular activation in brain stem nuclei associated with autonomic function, including the dorsal vagal complex (DVC) and the ventral lateral medulla (VLM). Mice received a single intraperitoneal injection of TNFα and were processed 2 h later to identify immunoreactive c-Fos in brain stem nuclei as a measure of cellular activity. The number of c-Fos-immunoreactive cells increased after TNFα challenge within the DVC and VLM. Cells immunoreactive for c-Fos were concentrated lateral to the area postrema (AP), a circumventricular organ medial to the subdivision of the caudal portion of the nucleus of the solitary tract (cNTS) within the DVC. To examine the role of microglia in mediating cellular responses to peripheral TNFα, minocycline was administered into the fourth ventricle to decrease microglial function. Minocycline treatment reduced ionized calcium binding adapter molecule 1 (IBA-1) immunoreactivity in the AP and cNTS. When animals were challenged with TNFα after receiving minocycline, fewer c-Fos-positive cells were induced in the DVC and selectively in the rostral VLM. These findings highlight the spatial selectivity of cells in the brain stem to increased peripheral proinflammatory signaling, as well as the impact of resident microglia on autonomic circuitry responses.NEW & NOTEWORTHY This study investigates how peripheral tumor necrosis factor-alpha (TNFα) affects neuronal activity in autonomic nuclei of the brain stem and how microglia contribute to this response. Peripheral TNFα increased neuronal activation (c-Fos expression) in the dorsal vagal complex (DVC) and ventrolateral medulla (VLM), particularly near the area postrema. Inhibiting microglia with intracerebroventricular minocycline reduced both microglial markers and TNFα-induced neuronal activity, suggesting that microglia play a key role in modulating cytokine-driven autonomic signaling in the brain stem.

Listeria Monocytogenes Abscess in the Brain Stem.

Generation and characterization of POMC-tdTomato reporter human pluripotent stem cell lines.

Skull base chordomas and chondrosarcomas are rare bone tumors predominantly found in the petroclival areas and involve the cranial nerves, internal carotid arteries, and brain stem. Their clinical aggressiveness and high risk of recurrence necessitate multimodal treatments, including extensive surgical resection and high-dose radiotherapy. Surgery is commonly the first step in their treatment, and ABCD rules should be respected; anatomical preservation of the innocent nasal anatomy for potential repeated surgeries in case of recurrence, block-by-block resection, coverage of the intradural residual tumor to prevent surgical site dissemination and cerebrospinal fluid dissemination, and drilling of the marginal bone. Here, we present our surgical strategy for skull base chordomas and chondrosarcomas for radical surgical resection and extirpation of the tumor.

A brain stem circuit integrating reflexive and anticipatory salivation.

A dual-delivery nanotherapeutic strategy using chitosan-epigallocatechin-3-gallate nanoparticles encapsulated in exosomes: A novel approach to combat brain aging.

Introduction: Brain death is a devastating outcome defined as an irreversible loss of total brain function. Toxicologic mimics of brain death can include baclofen, bupropion, tricyclic antidepressants, and barbiturates. Description: A 55-year-old female was found unresponsive with a suicide note and an empty bottle of Baclofen. She was intubated and brought to the ED, where she was hypotensive and had no brain stem reflexes on physical examination. An apnea test was performed, and she had one spontaneous breath at minute 6, after which she was placed back on mechanical ventilation. Due to concern of reverse triggering during the test, a brain flow study was done which showed no blood flow to her brain. The patient was pronounced brain dead. Surprisingly, she woke up in the morning and was subsequently extubated and later discharged. Discussion: Baclofen toxicity results from losing the selectivity of only affecting spinal GABA receptors, to include GABA receptors in the brain, thus causing cerebral global hypoperfusion secondary to suppression of neuronal activity and metabolic demand—resulting in coma. Other symptoms include hypotension, seizures, and respiratory depression. Brain death is confirmed by criteria including absent brain-stem reflexes in the setting of neurological dysfunction, a positive apnea test, and exclusion of drug intoxication, hypothermia, hypotension, neuromuscular and medical disturbances that can confound clinical assessment. Confirmatory imaging (i.e. a brain blood flow study) is warranted if confounders are suspected or a clinical assessment is insufficient. Despite this patient undergoing brain blood flow study confirming the diagnosis, she later woke up and returned to her normal function after baclofen’s effects had worn off, which has approximately a half life of 4 hours. This case highlights the importance of taking toxicologic agents into consideration as brain-death mimics. Clinicians should remain aware of Baclofen toxicity as a brain-death mimic in clinical practice, especially with it being widely prescribed. In the clinical setting of brain death suspicion, it is important to take sufficient history, perform a thorough physical examination and follow proposed criteria before confirmation. This ensures minimizing unnecessary confirmatory tests as well.