Deafferentation of Olfactory Bulb in Subjects Dying with COVID-19

There have been clinical descriptions of diverse neurological effects in COVID-19 disease, involving up to 36% of patients. It appears likely that most of these are not caused by viral brain invasion but by systemic accompaniments of critical illness such as coagulopathy, deleteriously upregulated immune response, autoimmune mechanisms, hypoxia or multiorgan failure. Anosmia or hyposmia is present in a majority of COVID-19 patients, and there is early and severe involvement of the nasopharyngeal mucosa and olfactory epithelium. Preliminary studies by our group have found massive gene expression changes in olfactory bulb, but the magnitude of these changes are not different between subjects with detectable versus non-detectable olfactory bulb SARS-CoV-2 RNA. As spontaneous discharge of olfactory epithelial afferents dictates intra-olfactory bulb neurophysiological activity and connectivity, we hypothesized that olfactory bulb deafferentation during COVID-19 is responsible for a large fraction of our observed olfactory bulb transcriptional changes. As the olfactory marker protein (OMP-1) is a specific marker of olfactory epithelial afferents to the olfactory bulb and is severely depleted in animal model lesions of olfactory epithelium, we quantified OMP-1-immunoreactivity in the olfactory bulb of subjects dying with or without COVID-19. Additionally, we quantified olfactory bulb tyrosine hydroxylase (TH), which is often also reduced after olfactory epithelium lesions, and SNAP-25, a pan-synaptic marker. COVID-19 cases (n = 18) were generally elderly and were not significantly different in age or gender distribution from the non-COVID-19 cases (n = 28). Both COVID-19 and non-COVID-19 cases had a wide range of neuropathological diagnoses. The area occupied by OMP-1 immunoreactivity in COVID-19 cases was significantly less, about 60% of that in control cases but amongst subjects with COVID-19, there was no significant difference between OBT-SARS-CoV-2-PCR-positive and negative cases. There were no significant group differences for TH or SNAP-25, supporting a selective effect for OMP-1. We suggest that olfactory dysfunction, and some of the COVID-19-associated transcriptional changes that we have reported for the olfactory bulb and amygdala, may be due to olfactory bulb deafferentation and subsequent transsynaptic effects. Additionally, animal models of olfactory bulb deafferentation or bulbectomy indicate a possibility for widespread changes in interconnected brain regions, providing a possible substrate for diverse post-acute COVID-19 neurological sequelae.

CONSEQUENCES OF CHILDREN SWALLOWING FOREIGN BODIES IN THE FORM OF MAGNETIC BALLS

The authors draw attention to dangerous children's toys – magnetic balls (MB). When MB is swallowed in the gastrointestinal tract (GIT), they can connect with each other in chains or are attracted to each other through the intestinal wall, forming necrosis and perforation of hollow organs at the junction. The authors cite four clinical cases of patients aged 2 to 8 years with varying degrees of severity of pathology caused by magnetic foreign bodies in GIT, from spontaneous discharge of foreign bodies during vomiting to multiple perforations of GIT.

Ketamine-xylazine anesthesia depth affects auditory neuronal responses in the lateral superior olive complex of the gerbil

Studies of in vivo neuronal responses to auditory inputs in the superior olive complex (SOC) are usually done under anesthesia. However, little attention has been paid to the effect of anesthesia itself on response properties. Here, we assessed the effect of anesthesia depth under ketamine-xylazine anesthetics on auditory evoked response properties of lateral SOC neurons. Anesthesia depth was tracked by monitoring EEG spectral peak frequencies. An increase in anesthesia depth led to a decrease in spontaneous discharge activities and an elevated response threshold. The temporal responses to suprathreshold tones were also affected, with adapted responses reduced but peak responses unaffected. Deepening the anesthesia depth also increased first spike latency. However, spike jitter was not affected. Auditory brainstem responses to clicks confirmed that ketamine-xylazine anesthesia depth affects auditory neuronal activities and the effect on spike rate and spike timing persists through the auditory pathway. We concluded from those observations that ketamine-xylazine affects lateral SOC response properties depending on the anesthesia depth.

Spontaneous Afferent Activity Carves Olfactory Circuits

Electrical activity has a key role in shaping neuronal circuits during development. In most sensory modalities, early in development, internally generated spontaneous activity sculpts the initial layout of neuronal wiring. With the maturation of the sense organs, the system relies more on sensory-evoked electrical activity. Stimuli-driven neuronal discharge is required for the transformation of immature circuits in the specific patterns of neuronal connectivity that subserve normal brain function. The olfactory system (OS) differs from this organizational plan. Despite the important role of odorant receptors (ORs) in shaping olfactory topography, odor-evoked activity does not have a prominent role in refining neuronal wiring. On the contrary, afferent spontaneous discharge is required to achieve and maintain the specific diagram of connectivity that defines the topography of the olfactory bulb (OB). Here, we provide an overview of the development of olfactory topography, with a focus on the role of afferent spontaneous discharge in the formation and maintenance of the specific synaptic contacts that result in the topographic organization of the OB.

Probing adaptation and spontaneous firing in human auditory-nerve fibers with far-field peri-stimulus time responses

Information in sound stimuli is conveyed from sensory hair cells to the cochlear nuclei by the firing of auditory nerve fibers (ANFs). For obvious ethical reasons, single unit recordings from the cochlear nerve have never been performed in human, thus functional hallmarks of ANFs are unknown. By filtering and rectifying the electrical signal recorded at the round window of gerbil cochleae, we reconstructed a peri-stimulus time response (PSTR), with a waveform similar to the peri-stimulus time histograms (PSTHs) recorded from single ANFs. Pair-by-pair analysis of simultaneous PSTR and PSTH recordings in gerbil provided a model to predict the rapid adaptation and spontaneous discharge rates (SR) in a population of ANFs according to their location in the cochlea. We then probed the model in the mouse, in which the SR-based distribution of ANFs differs from the gerbil. We show that the PSTR-based predictions of the rapid adaptation time constant and mean SR across frequency again matched those obtained by recordings from single ANFs. Using PSTR recorded from the human cochlear nerve in 8 normal-hearing patients who underwent cerebellopontine angle surgeries for a functional cranial-nerve disorders (trigeminal neuralgia or hemifacial spasm), we predicted a rapid adaptation of about 3 milliseconds and a mean SR of 23 spikes/s in the 4 kHz frequency range in human ANFs. Together, our results support the use of PSTR as a promising diagnostic tool to map the auditory nerve in humans, thus opening new avenues to better understanding neuropathies, tinnitus, and hyperacusis.

The effect of external ventricular drain tunneling length on CSF infection rate in pediatric patients: a randomized, double-blind, 3-arm controlled trial

OBJECTIVE The role of tunneling an external ventricular drain (EVD) more than the standard 5 cm for controlling device-related infections remains controversial. METHODS This is a randomized, double-blind, 3-arm controlled trial done in the Children’s Medical Center in Tehran, Iran. Pediatric patients (< 18 years old) with temporary hydrocephalus requiring an EVD and no evidence of CSF infection or prior EVD insertion were enrolled. Patients were randomly assigned (1:1:1) into the following arms: 5-cm (standard; group A); 10-cm (group B); or 15-cm (group C) EVD tunnel lengths. The investigators, parents, and person performing the analysis were masked. The surgeon was informed of the length of the EVD by the monitoring board just before operation. Patients were followed until the EVD’s fate was established. Infection rate and other complications related to EVDs were assessed. RESULTS A total of 105 patients were enrolled in three random groups (group A = 36, group B = 35, and group C = 34). The EVD was removed because there was no further need in most cases (67.6%), followed by conversion to a new EVD or ventriculoperitoneal shunt (15.2%), infection (11.4%), and spontaneous discharge without further CSF diversion requirement (5.7%). No statistical difference was found in infection rate (p = 0.47) or EVD duration (p = 0.81) between the three groups. No group reached the efficacy point sooner than the standard group (group B: hazard ratio 1.21, 95% CI 0.75–1.94, p = 0.429; group C: hazard ratio 1.03, 95% CI 0.64–1.65, p = 0.91). CONCLUSIONS EVD tunnel lengths of 5 cm and longer did not show a difference in the infection rate in pediatric patients. Indeed, tunneling lengths of 5 cm and greater seem to be equally effective in preventing EVD infection. Clinical trial registration no.: IRCT20160430027680N2 (IRCT.ir)

The Neurophysiological Impact of Experimentally-Induced Pain on Direct Muscle Spindle Afferent Response: A Scoping Review

Background: Musculoskeletal pain disorders are among the leading causes of years lived with disability worldwide representing a significant burden to society. Studies investigating a “nociceptive-fusimotor” relationship using experimentally-induced pain/noxious stimuli and muscle spindle afferent (MSA) response have been published over several decades. The purpose of this scoping review was to systematically identify and summarize research findings related to the impact of experimentally-induced pain or noxious stimulation on direct MSA discharge/response.Methods: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane and Embase were searched from database inception to August 2020. Eligible studies were: (a) published in English; (b) clinical or pre-clinical studies; (c) original data studies; (d) included the investigation of MSA response to experimentally-induced pain or noxious stimulation; (e) included quantification of at least one direct physiological measure associated with MSA activity/response. Two-phase screening procedures were conducted by a pair of independent reviewers and data extracted from eligible studies.Results: The literature search resulted in 195 articles of which 23 met inclusion criteria. Six studies (26%) were classified as clinical and 17 (74%) as pre-clinical. Two clinical studies investigated the effects of sacral dermatome pin-pricking on MSA response, while the remaining 4 studies investigated the effects of tonic muscle and/or skin pain induced by injection/infusion of hypertonic saline into the tibialis anterior muscle or subdermal tissues. In pre-clinical studies, muscle pain was induced by injection of noxious substances or the surgical removal of the meniscus at the knee joint.Conclusion: Clinical studies in awake humans reported that experimentally-induced pain did not affect, or else slightly decreased MSA spontaneous discharge and/or response during weak dorsiflexor muscle contraction, thus failing to support an excitatory nociceptive-fusimotor relationship. However, a majority of pre-clinical studies indicated that ipsilateral and contralateral muscle injection of noxious substances altered MSA resting discharge and/or response to stretch predominately through static fusimotor reflex mechanisms. Methodological differences (use of anesthesia, stretch methodology, etc.) may ultimately be responsible for the discrepancies between clinical and pre-clinical findings. Additional investigative efforts are needed to reconcile these discrepancies and to clearly establish or refute the existence of nociceptive-fusimotor relationship in muscular pain.

Ginkgolide B Maintains Calcium Homeostasis in Hypoxic Hippocampal Neurons by Inhibiting Calcium Influx and Intracellular Calcium Release

Ginkgolide B (GB), a terpene lactone and active ingredient of Ginkgo biloba, shows protective effects in neuronal cells subjected to hypoxia. We investigated whether GB might protect neurons from hypoxic injury through regulation of neuronal Ca2+ homeostasis. Primary hippocampal neurons subjected to chemical hypoxia (0.7 mM CoCl2) in vitro exhibited an increase in cytoplasmic Ca2+ (measured from the fluorescence of fluo-4), but this effect was significantly diminished by pre-treatment with 0.4 mM GB. Electrophysiological recordings from the brain slices of rats exposed to hypoxia in vivo revealed increases in spontaneous discharge frequency, action potential frequency and calcium current magnitude, and all these effects of hypoxia were suppressed by pre-treatment with 12 mg/kg GB. Western blot analysis demonstrated that hypoxia was associated with enhanced mRNA and protein expressions of Cav1.2 (a voltage-gated Ca2+ channel), STIM1 (a regulator of store-operated Ca2+ entry) and RyR2 (isoforms of Ryanodine Receptor which mediates sarcoplasmic reticulum Ca2+ release), and these actions of hypoxia were suppressed by GB. Taken together, our in vitro and in vivo data suggest that GB might protect neurons from hypoxia, in part, by regulating Ca2+ influx and intracellular Ca2+ release to maintain Ca2+ homeostasis.

What is the true discharge rate and pattern of the striatal projection neurons in Parkinson’s disease and Dystonia?

Dopamine and striatal dysfunctions play a key role in the pathophysiology of Parkinson’s disease (PD) and Dystonia, but our understanding of the changes in the discharge rate and pattern of striatal projection neurons (SPNs) remains limited. Here, we recorded and examined multi-unit signals from the striatum of PD and dystonic patients undergoing deep brain stimulation surgeries. Contrary to earlier human findings, we found no drastic changes in the spontaneous discharge of the well-isolated and stationary SPNs of the PD patients compared to the dystonic patients or to the normal levels of striatal activity reported in healthy animals. Moreover, cluster analysis using SPN discharge properties did not characterize two well-separated SPN subpopulations, indicating no SPN subpopulation-specific (D1 or D2 SPNs) discharge alterations in the pathological state. Our results imply that small to moderate changes in spontaneous SPN discharge related to PD and Dystonia are likely amplified by basal ganglia downstream structures.

Vasoactive Intestinal Polypeptide in the Carotid Body—A History of Forty Years of Research. A Mini Review

Vasoactive intestinal polypeptide (VIP) consists of 28 amino acid residues and is widespreadin many internal organs and systems. Its presence has also been found in the nervous structuressupplying the carotid body not only in mammals but also in birds and amphibians. The numberand distribution of VIP in the carotid body clearly depends on the animal species studied;however, among all the species, this neuropeptide is present in nerve fibers around blood vesselsand between glomus cell clusters. It is also known that the number of nerves containing VIP locatedin the carotid body may change under various pathological and physiological factors. The knowledgeconcerning the functioning of VIP in the carotid body is relatively limited. It is known that VIP mayimpact the glomus type I cells, causing changes in their spontaneous discharge, but the main impactof VIP on the carotid body is probably connected with the vasodilatory eects of this peptide and itsinfluence on blood flow and oxygen delivery. This review is a concise summary of forty years ofresearch concerning the distribution of VIP in the carotid body.