Novel Cellular Stress Models with Implications in Understanding and Treating ENT Pathologies

Interaction with the world around us requires extracting meaningful signals to guide behaviour. The mammalian senses of olfaction, vision, somatosensation, hearing, balance and taste facilitate extraction of sense-specific information. Most sensory organs in the vertebrate head originate from cranial placodes (CPs). CPs are formed embryonically through a series of differentiation steps arising at the boundary between neural and non-neural ectoderm, and they can be divided into anterior, posterior and intermediate groups depending on their place of origin in the developing embryonic head. Anterior CPs include adenohypophyseal, olfactory and lens placodes;intermediate CPs include the trigeminal placode, which gives rise to the sensory neurons of the ophthalmic and maxilla-mandibular divisions of the trigeminal ganglion;posterior CPs are comprised of the otic, lateral line placode and the epibranchial placodes that give rise to the inner ear, lateral line organs (in fish and amphibian) and sensory neurons of the geniculate, petrosal and nodose ganglia, respectively. The complexity of neural plate border specification in vitro poses a major limitation to gain deeper mechanistic insights into the developmental cues driving efficient placodal differentiation;hence generation and establishment of in vitro cellular models with improved cranial placode differentiation are challenging. Our group is interested in the establishment of cranial/sensory placodes in vitro using novel cellular stress stem cell reprogramming models with translational implications in sensorineural hearing loss regeneration and modelling COVID-19-associated anosmia. We are primarily interested in building the otic placodes that can form viable otic vesicles in vitro, which can be further directed to generate cochlear/vestibular systems of inner ear and the sensory neurons of its associated vestibulocochlear ganglion. Given the copious involvement of serine proteases in COVID-19 pathogenesis, we are also encouraged to leverage our proteolytic stress cellular models towards establishment and characterization of novel olfactory epithelial neurospheres housing supporting cells, progenitor cells and sensory neurons for investigating cellular and molecular targets of COVID-19-associated anosmia. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022.

A Case Report on Heart Rate Variability Biofeedback and Postconcussion Syndrome: Healing the Autonomic Nervous System

Postconcussion syndrome is a devastating condition of the mind, body, and even personality. Mounting research demonstrates that heart rate variability biofeedback can help the concussed individual in three critical ways: (a) eliciting high amplitude oscillations in cardiovascular functions and thereby strengthening self-regulatory control mechanisms;(b) restoring autonomic balance;and (c) increasing the afferent impulse stream from the baroreceptors to restore balance between inhibitory and excitatory processes in the brain.

Angiotensin and pain

The role of the renin-angiotensin system in human pain is a complicated and controversial field, partly due to the complexities of the system itself, but also because of the diverse ways in which pain functions. Here, we focus on what is known about the angiotensins in pathological pain and describe the ongoing attempts to identify candidate modulators of clinical significance. Systemic angiotensin agonists and antagonists have effects in a number of neuropathic ailments, including some of the most medically intractable conditions, such as endocrine disorders, cancer, myopathies, and viral infections (such as COVID-19), apart from direct damage to the nervous system. These arise due to multiple physiological processes involving both neural and nonneural pathways that could be overcome with future research. In summary, it is clear that the angiotensins acting through their different receptors exercise both algesic and analgesic effects, but less clear how this diversity of responses arises. © 2023 Elsevier Inc. All rights reserved.

Emerging Roles of Type-I Interferons in Neuroinflammation, Neurological Diseases, and Long-Haul COVID.

Interferons (IFNs) are pleiotropic cytokines originally identified for their antiviral activity. IFN-α and IFN-ß are both type I IFNs that have been used to treat neurological diseases such as multiple sclerosis. Microglia, astrocytes, as well as neurons in the central and peripheral nervous systems, including spinal cord neurons and dorsal root ganglion neurons, express type I IFN receptors (IFNARs). Type I IFNs play an active role in regulating cognition, aging, depression, and neurodegenerative diseases. Notably, by suppressing neuronal activity and synaptic transmission, IFN-α and IFN-ß produced potent analgesia. In this article, we discuss the role of type I IFNs in cognition, neurodegenerative diseases, and pain with a focus on neuroinflammation and neuro-glial interactions and their effects on cognition, neurodegenerative diseases, and pain. The role of type I IFNs in long-haul COVID-associated neurological disorders is also discussed. Insights into type I IFN signaling in neurons and non-neuronal cells will improve our treatments of neurological disorders in various disease conditions.

Rapidly progressing idiopathic intracranial hypertension after a Covid-19 infection

AimsTo present a case of a previously well child with rapidly progressing idiopathic intracranial hypertension (IIH) requiring a lumboperitoneal shunt after a Covid-19 infection.MethodsA fifteen-year-old girl presented to the Children’s Emergency Department on 23th October 2021 with a history of headaches (temporal, periorbital and occipital) and reduced visual acuity. These started following a Covid-19 infection on 30th September. She was reviewed by ophthalmology in view of deteriorating visual acuity (right eye>left eye). Bilateral papilloedema and haemorrhages were noted on examination. Her visual acuity was 6/24 unaided in the right eye and 6/7.5 unaided in the left eye. During the admission her visual acuity deteriorated to 6/36 pinhole in the right eye and 6/12 pinhole in the left eye. In the right eye she lost colour vision and developed a relative afferent pupillary defect. She received acetazolamide and intravenous methylprednisolone before being transferred to Birmingham Children’s Hospital neurosurgical ward for a lumboperitoneal shunt.There has been a significant improvement since surgery. On 22nd November there was resolving papilloedema and haemorrhages. She had normalised colour vision and resolution of the afferent pupillary reflex. Her visual acuity was 0.275 in the right eye and 0.100 in the left eye (LogMAR). However, persistent deficits could have significant consequences such as the ability to obtain a driving licence.ResultsAn MRI showed bilateral papilloedema of the optic discs. An MRV showed narrowing of the bilateral traverse sinuses with gradual tapering suggestive of high intracranial pressure. Raised intracranial pressures were confirmed by lumbar puncture on two separate occasions. The pressures were beyond the limit of the manometer used (34cm H2O).ConclusionShe had two well recognised risk factors;female gender and increased BMI so is within the high-risk group. However, she had no pathognomonic signs/symptoms of IIH or Ophthalmic complaints before COVID-19, meaning this was a rapidly progressing case that coincided with a Covid-19 infection.It is not possible to declare a cause and effect relationship in this case, but there is some emerging reports of Covid-19 positive patients with refractory headaches having isolated raised intracranial pressures within the adult population.1 2The Covid-19 pandemic has also precipitated indirect consequences. Weight gain as a result of lockdown was reported, which increased her risk of IIH.ReferencesSilva MTT, Lima MA, Torezani G, et al. Isolated intracranial hypertension associated with COVID-19. Cephalalgia. 2020;40(13):1452-1458. doi:10.1177/0333102420965963Ilhan B, Cokal BG, Mungan Y. Intracranial hypertension and visual loss following COVID-19: A case report. Indian J Ophthalmol. 2021;69(6):1625-1627. doi:10.4103/ijo.IJO_342_21

Brain-based measures of nociception during general anesthesia with remifentanil: A randomized controlled trial

Background Catheter radiofrequency (RF) ablation for cardiac arrhythmias is a painful procedure. Prior work using functional near-infrared spectroscopy (fNIRS) in patients under general anesthesia has indicated that ablation results in activity in pain-related cortical regions, presumably due to inadequate blockade of afferent nociceptors originating within the cardiac system. Having an objective brain-based measure for nociception and analgesia may in the future allow for enhanced analgesic control during surgical procedures. Hence, the primary aim of this study is to demonstrate that the administration of remifentanil, an opioid widely used during surgery, can attenuate the fNIRS cortical responses to cardiac ablation. Methods and findings We investigated the effects of continuous remifentanil on cortical hemodynamics during cardiac ablation under anesthesia. In a randomized, double-blinded, placebo (PL)-controlled trial, we examined 32 pediatric patients (mean age of 15.8 years,16 females) undergoing catheter ablation for cardiac arrhythmias at the Cardiology Department of Boston Children’s Hospital from October 2016 to March 2020;9 received 0.9% NaCl, 12 received low-dose (LD) remifentanil (0.25 mcg/kg/min), and 11 received high-dose (HD) remifentanil (0.5 mcg/kg/min). The hemodynamic changes of primary somatosensory and prefrontal cortices were recorded during surgery using a continuous wave fNIRS system. The primary outcome measures were the changes in oxyhemoglobin concentration (NadirHbO, i.e., lowest oxyhemoglobin concentration and PeakHbO, i.e., peak change and area under the curve) of medial frontopolar cortex (mFPC), lateral prefrontal cortex (lPFC) and primary somatosensory cortex (S1) to ablation in PL versus remifentanil groups. Secondary measures included the fNIRS response to an auditory control condition. The data analysis was performed on an intention-to-treat (ITT) basis. Remifentanil group (dosage subgroups combined) was compared with PL, and a post hoc analysis was performed to identify dose effects. There were no adverse events. The groups were comparable in age, sex, and number of ablations. Results comparing remifentanil versus PL show that PL group exhibit greater NadirHbO in inferior mFPC (mean difference (MD) = 1.229, 95% confidence interval [CI] = 0.334, 2.124, p < 0.001) and superior mFPC (MD = 1.206, 95% CI = 0.303, 2.109, p = 0.001) and greater PeakHbO in inferior mFPC (MD = −1.138, 95% CI = −2.062, −0.214, p = 0.002) and superior mFPC (MD = −0.999, 95% CI = −1.961, −0.036, p = 0.008) in response to ablation. S1 activation from ablation was greatest in PL, then LD, and HD groups, but failed to reach significance, whereas lPFC activation to ablation was similar in all groups. Ablation versus auditory stimuli resulted in higher PeakHbO in inferior mFPC (MD = 0.053, 95% CI = 0.004, 0.101, p = 0.004) and superior mFPC (MD = 0.052, 95% CI = 0.013, 0.091, p < 0.001) and higher NadirHbO in posterior superior S1 (Pos. SS1;MD = −0.342, 95% CI = −0.680, −0.004, p = 0.007) during ablation of all patients. Remifentanil group had smaller NadirHbO in inferior mFPC (MD = 0.098, 95% CI = 0.009, 0.130, p = 0.003) and superior mFPC (MD = 0.096, 95% CI = 0.008, 0.116, p = 0.003) and smaller PeakHbO in superior mFPC (MD = −0.092, 95% CI = −0.680, −0.004, p = 0.007) during both the stimuli. Study limitations were small sample size, motion from surgery, indirect measure of nociception, and shallow penetration depth of fNIRS only allowing access to superficial cortical layers. Conclusions We observed cortical activity related to nociception during cardiac ablation under general anesthesia with remifentanil. It highlights the potential of fNIRS to provide an objective pain measure in unconscious patients, where cortical-based measures may be more accurate than current evaluation methods. Future research may expand on this application to produce a real-time indication of pain that will aid clinicians in providing immediate and adequate pain treatment. Trial registration ClinicalTrials.gov NCT02703090

Innate Receptors Expression by Lung Nociceptors: Impact on COVID-19 and Aging.

The lungs are constantly exposed to non-sterile air which carries harmful threats, such as particles and pathogens. Nonetheless, this organ is equipped with fast and efficient mechanisms to eliminate these threats from the airways as well as prevent pathogen invasion. The respiratory tract is densely innervated by sensory neurons, also known as nociceptors, which are responsible for the detection of external stimuli and initiation of physiological and immunological responses. Furthermore, expression of functional innate receptors by nociceptors have been reported; however, the influence of these receptors to the lung function and local immune response is poorly described. The COVID-19 pandemic has shown the importance of coordinated and competent pulmonary immunity for the prevention of pathogen spread as well as prevention of excessive tissue injury. New findings suggest that lung nociceptors can be a target of SARS-CoV-2 infection; what remains unclear is whether innate receptor trigger sensory neuron activation during SARS-CoV-2 infection and what is the relevance for the outcomes. Moreover, elderly individuals often present with respiratory, neurological and immunological dysfunction. Whether aging in the context of sensory nerve function and innate receptors contributes to the disorders of these systems is currently unknown. Here we discuss the expression of innate receptors by nociceptors, particularly in the lungs, and the possible impact of their activation on pulmonary immunity. We then demonstrate recent evidence that suggests lung sensory neurons as reservoirs for SARS-CoV-2 and possible viral recognition via innate receptors. Lastly, we explore the mechanisms by which lung nociceptors might contribute to disturbance in respiratory and immunological responses during the aging process.

The Cellular basis of loss of smell in 2019-nCoV-infected individuals.

A prominent clinical symptom of 2019-novel coronavirus (nCoV) infection is hyposmia/anosmia (decrease or loss of sense of smell), along with general symptoms such as fatigue, shortness of breath, fever and cough. The identity of the cell lineages that underpin the infection-associated loss of olfaction could be critical for the clinical management of 2019-nCoV-infected individuals. Recent research has confirmed the role of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) as key host-specific cellular moieties responsible for the cellular entry of the virus. Accordingly, the ongoing medical examinations and the autopsy reports of the deceased individuals indicate that organs/tissues with high expression levels of ACE2, TMPRSS2 and other putative viral entry-associated genes are most vulnerable to the infection. We studied if anosmia in 2019-nCoV-infected individuals can be explained by the expression patterns associated with these host-specific moieties across the known olfactory epithelial cell types, identified from a recently published single-cell expression study. Our findings underscore selective expression of these viral entry-associated genes in a subset of sustentacular cells (SUSs), Bowman's gland cells (BGCs) and stem cells of the olfactory epithelium. Co-expression analysis of ACE2 and TMPRSS2 and protein-protein interaction among the host and viral proteins elected regulatory cytoskeleton protein-enriched SUSs as the most vulnerable cell type of the olfactory epithelium. Furthermore, expression, structural and docking analyses of ACE2 revealed the potential risk of olfactory dysfunction in four additional mammalian species, revealing an evolutionarily conserved infection susceptibility. In summary, our findings provide a plausible cellular basis for the loss of smell in 2019-nCoV-infected patients.

Sensory modulation of airways immunity.

The airways are constantly exposed to a multitude of inhaled particles and, as such, require a finely tuned discrimination between harmful or potentially threatening stimuli, and discrete responses to maintain homeostasis. Both the immune and nervous systems have the ability to sense environmental (and internal) signals, to integrate the obtained information and to initiate a protective reaction. Lung immunity and innervation are known to be individually involved in these processes, but it is becoming clear that they can also influence one another via a multitude of complex mechanisms. Here, we specifically describe how sensory innervation affects airways immunity with a focus on pathological conditions such as asthma or infections, describing cellular and molecular mechanisms, and highlighting potentially novel therapeutic targets.

Anosmia: a missing link in the neuroimmunology of coronavirus disease 2019 (COVID-19).

Just before 2020 began, a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), brought for humans a potentially fatal disease known as coronavirus disease 2019 (COVID-19). The world has thoroughly been affected by COVID-19, while there has been little progress towards understanding the pathogenesis of COVID-19. Patients with a severe phenotype of disease and those who died from the disease have shown hyperinflammation and were more likely to develop neurological manifestations, linking the clinical disease with neuroimmunological features. Anosmia frequently occurs early in the course of COVID-19. The prevalence of anosmia would be influenced by self-diagnosis as well as self-misdiagnosis in patients with COVID-19. Despite this, the association between anosmia and COVID-19 has been a hope for research, aiming to understand the pathogenesis of COVID-19. Studies have suggested differently probable mechanisms for the development of anosmia in COVID-19, including olfactory cleft syndrome, postviral anosmia syndrome, cytokine storm, direct damage of olfactory sensory neurons, and impairment of the olfactory perception center in the brain. Thus, the observation of anosmia would direct us to find the pathogenesis of COVID-19 in the central nervous system, and this is consistent with numerous neurological manifestations related to COVID-19. Like other neurotropic viruses, SARS-CoV-2 might be able to enter the central nervous system via the olfactory epithelium and induce innate immune responses at the site of entry. Viral replication in the nonneural olfactory cells indirectly causes damage to the olfactory receptor nerves, and as a consequence, anosmia occurs. Further studies are required to investigate the neuroimmunology of COVID-19 in relation to anosmia.