First in-neonate use of non-invasive transcutaneous auricular vagus nerve stimulation: 18-month neurodevelopmental and sensory follow-up

Objective: Non-invasive transcutaneous auricular vagal nerve stimulation (taVNS) paired with oral feeding is a novel intervention for infants with feeding delays that may improve feeding and help avoid a gastrostomy tube (Gtube). However, the long-term impact of this neurostimulation on infant's development remains unknown. We investigated the neurodevelopmental and sensory outcomes of infants who received taVNS paired with bottle feeding. Method(s): Twenty-one of 35 toddlers who participated in the open label trial of taVNS paired with one or two feeds a day for 2-3 weeks, underwent comprehensive developmental assessments at 18 months of age using Cognitive Adaptive Test, Clinical Linguistics and Auditory Milestone, and Peabody gross motor scores. Twelve of those assessed achieved full oral feeds ('responders') and 9 had G-tube placed for feeds ('non-responders'). Before COVID, 12 toddlers (5 responders, 7 non-responders) were also assessed in the home using the Bayley-III and Sensory Profile (SP-2) assessments. Area deprivation index (ADI) was used to measure resource poor environments and relate to test scores. We used Fishers exact test and Pearson correlation coefficients to compare neurodevelopmental and sensory performance in responders versus non-responders. Result(s): taVNS responders showed significantly better general sensory processing in SP-2 than did non-responders (p =0.04). There were no significant differences in Bayley-III or CAT/CLAMS/ASQ scores in areas of cognition, receptive language, fine motor, and gross motor skills in this small sample size, but are similar to published scores for preterm infants who received G-tubes. ADI was not significantly associated with neurodevelopmental scores. Conclusion(s): These results suggest that taVNS paired with feeding may have a potential long-term positive neurodevelopmental effect on sensory processing in neonates with poor feeding. The current open-label results need testing in randomized controlled trials of taVNS paired with oral feeding in developmentally delayed infants failing oral feeds. Research Category and Technology and Methods Clinical Research: 12. Vagus Nerve Stimulation (VNS) Keywords: Neurodevelopment, taVNS, feeding, developmental delaysCopyright © 2023

COVID-19 and the autonomic nervous system

Background: COVID-19 infection has been shown to have an adverse impact on the cardiovascular system. Cardiac injury, as indicated by elevated cardiac troponin and NT-proBNP levels have been confirmed in COVID-19 cases. There is still ambivalent data on the effect of left ventricular function. Cases of left ventricular impairment, persistent hypotension, acute myopericarditis, myocarditis, arrhythmia and heart failure have been reported in the short term, but there is a significant lacuna when it comes to medium and long-term follow-up of subjects previously infected with COVID-19. Purpose(s): To assess any residual myocardial and autonomic injury in subjects previously infected with COVID-19 at a median follow-up of 5 months. Method(s): A case-control study was performed. Cases were randomly selected subjects who were previously diagnosed with COVID-19 infection following nasopharyngeal swabbing. Controls were subjects who had not been found to be infected with COVID-19 following swabbing and were negative for COVID-19 IgG antibodies. All participants were submitted a standardised questionnaire regarding past medical history. Blood investigations were taken including NT-proBNP and troponin I levels. In addition, all participants underwent 24-hour ambulatory blood pressure monitoring (ABPM) and 24-hour ECG monitoring. The latter was used to assess both for underlying arrhythmias as well as heart rate variability (HRV), a measure of autonomic regulation of the heart. All data was analysed using SPSS version 23.0. Result(s): The study comprised 259 subjects, whereby cases included 174 participants while 75 subjects were age- and gender-matched controls. The study cohort was relatively young with a mean age of 46.1+/-13.8 years. The median follow-up was of approximately 5 months (median 173.5 days, IQR 129-193.25 days). There was no statistically significant difference between cases and controls with regards cardiovascular risk factors and underlying medical conditions. Likewise, there was no difference in blood investigations, including troponin I and NT-proBNP levels at 5-months followup. No difference was noted between the two groups in both awake and asleep blood pressure (BP) readings, as well as dipping BP status. No significant arrhythmias were noted in both groups on 24-hour ECG monitoring. However, when assessing for heart rate variability, it was shown that subjects who had been previously infected with COVID-19 exhibited lower root-mean square differences of successive R-R intervals (RMSSD), p=0.028. This indicates poor vagus nerve-mediated autonomic control of the heart. Conclusion(s): Subjects previously infected with COVID-19 exhibited lower HRV as exhibited by low RMSSD as compared to controls. Reduced HRV is a known biomarker for mortality and sudden death in cardiac disease. The possible long-term implications of reduced HRV in subjects previously infected with COVID-19 merits further investigation.

Clinical applications of transcutaneous auricular neurostimulation for opioid use disorder and pain

Symposium title: Addressing chronic pain and the opioid epidemic using auricular neuromodulation Symposium description: Our proposed symposium integrates a diverse group of scientist and clinician experts (Drs. Cunningham, Wilkes, Khodaparast, Badran) who have committed to exploring the anti-nociceptive and opioid sparing effects of auricular neuromodulation to progress toward non-opioid interventions for chronic pain and opioid use disorders. The demand for chronic pain therapies has increased at an unprecedented rate over the last several decades, contributing in part to a surge in prescription and illicit opioid demand. Countless patients were escalated to prolonged, high-dose opioid regimens over years of treatment. By 2014, 5.4% of U.S. adults were estimated to use prescription opioids on a long-term basis. As the harms of opioid proliferation became increasingly clear, a dramatic paradigm shift occurred in which these drugs are now perceived as more dangerous than beneficial for chronic pain. New clinical guidelines highlight the risks of high-dose regimens as well as the limited benefits, particularly insufficient analgesia and hyperalgesia, associated with long-term use. According to this new perspective, the preferred therapeutic modality for many patients is to safely taper, or even completely stop, using opioids. Transcutaneous auricular neurostimulation (tAN) is a novel therapeutic paradigm that includes stimulation of both the auricular branch of the vagus nerve and auriculotemporal nerve (branch of trigeminal). tAN therapy results in clinically significant reductions in opioid withdrawal symptoms associated with opioid detoxification and tapering. Either adjunctive vagal or trigeminal stimulation modulates pain transmission suggesting overlapping common effector pathways, possibly targeting the endogenous opioid system, which could lead to a synergistic therapeutic benefit for pain. This symposium will explore the scientific basis for this hypothesis across targeted and interconnected topics, including fundamental neuropharmacological mechanisms underlying pain and opioids, clinical challenges of tapering opioids, managing opioid withdrawal symptoms with tAN, and the prospects for tAN to deliver a safe alternative treatment option for pain disorders. The United States is experiencing an epidemic for prescription and non-prescription opioids, which have continued to rise since the 1990s. During 2015, approximately 2.1 million people were severely dependent on prescription opioids, and 513,000 on heroin. In 2020, the Centers for Disease Control reported 93,331 substance use overdose deaths. The continuing increase in opioid-related deaths from 2015 (18%) to 2020 (60%) is partly attributed to the mental health crisis during the Covid-19 pandemic. Aside from pain mitigation, individuals with opioid use disorder (OUD) may be motivated to continue drug-seeking by both the positive reinforcement of the euphoric effects of opioids and the negative reinforcement of opioid withdrawal symptoms due to cessation. Alternative approaches for OUD are a major priority for government agencies given the substantial impact on health, social, and economic welfare. Transcutaneous auricular neurostimulation (tAN) is a non-invasive form of vagus and trigeminal neuromodulation that was recently proven to be an efficacious non-pharmacologic based treatment for reducing opioid withdrawal symptoms. In 2021, tAN therapy received FDA clearance as an adjunctive treatment for opioid withdrawal symptoms in adults. tAN therapy was also proven safe and effective in reducing symptoms of neonatal opioid withdrawal syndrome (NOWS) in neonates. tAN as an adjuvant was safe, well-tolerated, while facilitating the successful rapid weaning of oral morphine and decreasing length of stay in the neonatal ICU. Based on these preliminary findings, tAN therapy is currently in two NIH-funded pivotal clinical trials to: 1) evaluate the long-term effects of tAN on opioid use relapse prevention and cravings in adults with OUD, and 2) determine f tAN therapy can reduce withdrawal symptoms and reduce morphine length of treatment for neonates with NOWS. Lastly, we will explore how tAN could be utilized as neuromodulatory approach for opioid sparing, and ultimately pain mitigation. Research Category and Technology and Methods Clinical Research: 12. Vagus Nerve Stimulation (VNS) Keywords: Vagus Nerve Stimulation, Opioid Use Disorder, Pain, NeurostimulationCopyright © 2023

Transjugular Approach for Recurrent Intracranial Glomus Vagale Tumors: An Ideal Approach to Preserve Hearing and Facial Nerve Function

Lateral skull base paragangliomas (glomus tumors) are rare skull base tumors arising from neuroendocrine cells. These benign tumors can be locally aggressive with potential for intracranial extension and significant morbidity as they compromise cranial nerve structures. Treatment is highly patient dependent. Herein, we present a case of recurrent glomus vagale paraganglioma requiring a multidisciplinary transjugular and transcervical approach for complete resection. A 64-year-old male was referred to the neurotology clinic in 2019 for a left skull base tumor causing progressive dysphonia and dysphagia. Exam revealed left true vocal fold weakness and no other abnormalities. Hearing was normal on the left. Magnetic resonance imaging (MRI) revealed a large hyperintense lesion of the left jugular foramen with intracranial cerebellopontine angle extension and normal flow through the sigmoid sinus and jugular vein. The patient elected for surgical removal and near-total resection was achieved via retrosigmoid craniotomy. A small portion was intentionally left in the jugular foramen to preserve the intact eleventh cranial nerve, internal jugular vein, and sigmoid sinus. Surgical pathology confirmed glomus paraganglioma. Postoperative radiation was strongly recommended, but the patient was lost to follow-up due to the COVID-19 pandemic. The patient re-presented in late 2021 with worsened dysphonia and dysphagia. Exam confirmed left true vocal fold immobility consistent with vagal nerve paralysis and a new finding of left tongue weakness consistent with hypoglossal nerve injury. MRI revealed recurrence of the lesion to dimensions larger than original presentation and complete occlusion of the sigmoid-jugular system. Hearing and facial nerve function remained fully intact, thus a transjugular approach with hearing preservation and complete surgical resection was utilized. After combined retrosigmoid and transcervical incision, the transjugular approach was utilized to resect the sigmoid sinus, the tumor of the jugular foramen, and the intracranial extension. The ear canal and facial nerve canal were preserved. The sigmoid sinus was ligated with surgical clips and the jugular vein was ligated with suture thread. Intracranially, the hypoglossal nerve was identified and preserved, and the vagus nerve was seen eroded by tumor. Pathology confirmed recurrent paraganglioma. Postoperatively, the patient recovered well but continues to endorse persistent dysphonia. His treatment plan includes radiation and thyroplasty. Multiple surgical approaches for the treatment of skull base paragangliomas have been reported including infratemporal types A to D, among others. This report identifies a rare case of recurrent paraganglioma which necessitated removal via transjugular approach. While uncommon in skull base surgery, this approach allowed identification and preservation of important neck and skull base structures (e.g., facial nerve, ear canal, spinal accessory nerve) while achieving complete gross resection. Radiation techniques have become popular alternatives for treatment of glomus tumors of the skull base due to high levels of surgery-related adverse events. Thus, skull base surgeons should be aware of the utility of the transjugular surgical technique for patients with intact hearing and facial nerve function who seek removal of intracranial jugular foramen tumors.

Gastrointestinal, Respiratory, and Olfactory Neurotropism of Sars-Cov2 as a Possible Trigger of Parkinson's Disease: Is a Multi-Hit Multi-Step Process on the Cards.

Since the first emergence of COVID-19 on the global stage, there has been a wealth of evidence to suggest that SARS-Cov2 is not merely a pulmonary pathogen. This virus is unique in its ability to disrupt cellular pathways related to protein homeostasis, mitochondrial function, stress response, and aging. Such effects raise concerns about the long-term fate of survivors of COVID-19 infection, particularly regarding neurodegenerative diseases. The concept of interaction between environmental factors and alpha-synuclein formation in the olfactory bulb and vagal autonomic terminals with subsequent caudo-cranial migration has received much attention in the context of PD pathogenesis. Anosmia and gastrointestinal symptoms are two well-known symptoms of COVID-19, with evidence of an olfactory bulb and vagal infiltration by SARS-CoV2. This raises the possibility of the spread of the viral particles to the brain along multiple cranial nerve routes. Neurotropism, coupled with the ability of the SARS-Cov2 virion to induce abnormal protein folding and stress responses in the central nervous system, in presence of an inflammatory milieu, reinforced by hypoxia, coagulopathy, and endothelial dysfunction, reverberates the intriguing possibility of activation of a neurodegenerative cascade leading to the development of pathological alpha-synuclein aggregates and thus, triggering the development of PD in survivors of COVID19. This review attempts to summarize and critically appraise existing evidence from basic science research and clinical reports of links between COVID-19 and PD and explores the prospect of a multi-hit pathophysiological process, induced by SARS-Cov2 infection, ultimately converging on perturbed cellular protein homeostasis, which although is intriguing, presently lacks robust evidence for confirmation.

The diversity of neuro-immune circuits controlling lung inflammation.

It is becoming increasingly appreciated that the nervous and immune systems communicate bidirectionally to regulate immunological outcomes in a variety of organs including the lung. Activation of neuronal signaling can be induced by inflammation, tissue damage, or pathogens to evoke or reduce immune cell activation in what has been termed a neuro-immune reflex. In the periphery, these reflexes include the cholinergic anti-inflammatory pathway, sympathetic reflex, and sensory nociceptor-immune cell pathways. Continual advances in neuroimmunology in peripheral organ systems have fueled small-scale clinical trials that have yielded encouraging results for a range of immunopathologies such as rheumatoid arthritis. Despite these successes, several limitations should give clinical investigators pause in the application of neural stimulation as a therapeutic for lung inflammation, especially if inflammation arises from a novel pathogen. In this review, the general mechanisms of each reflex, the evidence for these circuits in the control of lung inflammation, and the key knowledge gaps in our understanding of these neuroimmune circuits will be discussed. These limitations can be overcome not only through better understanding of neuroanatomy but also through a systematic evaluation of stimulation parameters using immune activation in lung tissues as primary readouts. Our rapidly evolving understanding of the nervous and immune systems highlights the importance of bidirectional communication between these cells in health and disease. This integrative approach has tremendous potential in the development of targeted therapeutics, if specific challenges can be overcome.

Cholinergic dysfunction in COVID-19: frantic search and hoping for the best.

A novel coronavirus known as severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a potential cause of acute respiratory infection called coronavirus disease 2019 (COVID-19). The binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) induces a series of inflammatory cellular events with cytopathic effects leading to cell injury and hyperinflammation. Severe SARS-CoV-2 infection may lead to dysautonomia and sympathetic storm due to dysfunction of the autonomic nervous system (ANS). Therefore, this review aimed to elucidate the critical role of the cholinergic system (CS) in SARS-CoV-2 infection. The CS forms a multi-faceted network performing diverse functions in the body due to its distribution in the neuronal and non-neuronal cells. Acetylcholine (ACh) acts on two main types of receptors which are nicotinic receptors (NRs) and muscarinic receptors (MRs). NRs induce T cell anergy with impairment of antigen-mediated signal transduction. Nicotine through activation of T cell NRs inhibits the expression and release of the pro-inflammatory cytokines. NRs play important anti-inflammatory effects while MRs promote inflammation by inducing the release of pro-inflammatory cytokines. SARS-CoV-2 infection can affect the morphological and functional stability of CS through the disruption of cholinergic receptors. SARS-CoV-2 spike protein is similar to neurotoxins, which can bind to nicotinic acetylcholine receptors (nAChR) in the ANS and brain. Therefore, cholinergic receptors mainly nAChR and related cholinergic agonists may affect the pathogenesis of SARS-CoV-2 infection. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. As well, nAChR activators through interaction with diverse signaling pathways can reduce the risk of inflammatory disorders in COVID-19. In addition, nAChR activators may mitigate endothelial dysfunction (ED), oxidative stress (OS), and associated coagulopathy in COVID-19. Similarly, nAChR activators may improve OS, inflammatory changes, and cytokine storm in COVID-19. Therefore, nAChR activators like varenicline in virtue of its anti-inflammatory and anti-oxidant effects with direct anti-SARS-CoV-2 effect could be effective in the management of COVID-19.

Case Report: Auricular vagus nerve stimulation possibly alleviates COVID-19 disease on a high-risk patient.

Introduction: SARS-CoV-2 is a highly contagious virus that was identified as the cause of COVID-19 disease in early 2020. The infection is clinically similar to interstitial pneumonia and acute respiratory distress syndrome (ARDS) and often shows cardiovascular damage. Patients with cardiovascular risk factors are more prone to COVID-19 disease and their sequelae. Due to the anti-inflammatory effect and the improvement in pulmonary function, auricular vagus nerve stimulation (aVNS) therapy might alleviate a COVID-19 infection. Patient and Methods: A high-risk patient with cardiovascular diseases and Implantable Cardioverter Defibrillator (ICD), type 2 diabetes and peripheral arterial disease IV, according to Rutherford`s classification, became infected with COVID-19. The patient underwent wound surgery because of an infected necrosis with a methicillin-resistant Staphylococcus aureus (MRSA) of his small toe and was already on aVNS therapy to relieve his leg pain and improve microcirculation. AVNS was performed with the AuriStim device (Multisana GmbH, Austria), which stimulates vagally innervated regions of the auricle by administering electrical stimulation via percutaneous electrodes for 6 weeks. Results: The multimorbid high-risk patient, who was expected to go through a severe course of the COVID-19 disease, showed hardly any symptoms during ongoing aVNS therapy, while other family members, being much younger and healthy suffered from a more serious course with headache, pneumonia and general weakness. Conclusion: The auricular vagus nerve stimulation is a clinically tested and safe procedure and might represent an alternative and effective way of treating COVID-19 disease. Nevertheless, due to several limitations of this case report, randomized controlled studies are needed to evaluate the efficacy of aVNS therapy on COVID-19 disease.

A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation.

Long COVID, the postviral disorder caused by COVID-19, is expected to become one of the leading causes of disability in Europe. The cognitive consequences of long COVID have been described as "brain fog" and characterized by anxiety and depression, and by cognitive deficits. Long COVID is assumed to be a complex condition arising from multiple causes, including persistent brainstem dysfunction and disrupted vagal signaling. We recommend the potential application of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON instrument to compensate for the cognitive decline and to ameliorate affective symptoms caused by long COVID. This technique enhances vagal signaling by directly activating the nuclei in the brainstem, which are hypoactive in long COVID to enhance mood and to promote attention, memory, and cognitive control-factors affected by long COVID. Considering that atVNS is a non-pharmacological intervention, its ADD-ON to standard pharmaceutical agents will be useful for non-responders, making of this method a suitable tool. Given that atVNS can be employed as an ecological momentary intervention (EMI), we outline the translational advantages of atVNS in the context of accelerating the cognitive and affective recovery from long COVID.

Effect of Peripheral Neuromodulation on Headache in Post Covid-19 Survivors

Objective: The purpose of present study was to evaluate the impact of peripheral neuromodulation through vagus nerve stimulation on headache in Post COVID-19 survivors. Method(s): Thirty Post COVID-19 survivors from both genders (17 females and 13 males) aged from 20 to 40 years who suffered from Post COVID-19 headache were recruited and randomized into two groups of equal number. Subjects in group A (study group) received transcutaneous vagus nerve stimulation as well as the designed physiotherapy program whereas subjects in group B (control group) underwent placebo transcutaneous vagus nerve stimulation on vagus nerve in addition to the same designed physical therapy program. The treatment was carried-out for 5 sessions each week for four weeks. Visual analogue scale (VAS) was used to measure the intensity of headache pain whereas the headache disability index (HDI) was used to measure the disability resulted from headache. Result(s): The findings showed significant decline in VAS and HDI post treatment in study group (A) and control group (B) in comparison with that pretreatment (p<0.001). Between-group analysis showed no significant difference between the two groups pretreatment (p>0.05), whereas there was significant decline in VAS and HDI in study group in comparison with that of the control group posttreatment (p<0.05). Conclusion(s): peripheral neuromodulation is more effective in managing headache in post COVID-19 survivors. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Transcutaneous auricular vagus nerve stimulation effects on inflammatory markers and clinical evolution of patients with COVID-19: a pilot randomized clinical trial.

OBJECTIVE: To evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammatory markers and clinical outcomes in patients with COVID-19. METHODS: A randomized blinded pilot study was carried out with 21 individuals hospitalized with COVID-19 who received 14 sessions of active (a-taVNS) or sham taVNS (s-taVNS). The level of interleukin-6 (IL-6), interleukin-10 (IL-10), cortisol, and C-reactive protein (CRP) in plasma and clinical evolution pre- and post-intervention were evaluated. The memory and attention levels were evaluated 14 days after the end of the treatment. RESULTS: After treatment, significant intragroup differences were found in the CRP (p = 0.01), IL-6 (p = 0.01), and cortisol (p = 0.01) levels; however, in the comparison between the groups, only the CRP level was statistically lower for the a-taVNS (p = 0.04). The impression of improvement in memory and attention was greater in the a-taVNS than in the s-taVNS (p = 0.01, p = 0.04, respectively). There was no difference between the other clinical outcomes. CONCLUSIONS: taVNS is a viable and safe intervention in the acute care of patients with COVID-19, which can modulate their inflammatory profile and improve cognitive symptoms. However, improvements in overall clinical outcomes were not detected. Larger sample sizes and longer follow-ups are needed to confirm the anti-inflammatory and clinical effects of taVNS in patients with COVID-19. TRIALS REGISTRY: The Brazilian Registry of Clinical Trials (RBR-399t4g5).

Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration?

Following a SARS-CoV-2 infection, many individuals suffer from post-COVID-19 syndrome. It makes them unable to proceed with common everyday activities due to weakness, memory lapses, pain, dyspnea and other unspecific physical complaints. Several investigators could demonstrate that the SARS-CoV-2 related spike glycoprotein (SGP) attaches not only to ACE-2 receptors but also shows DNA sections highly affine to nicotinic acetylcholine receptors (nAChRs). The nAChR is the principal structure of cholinergic neuromodulation and is responsible for coordinated neuronal network interaction. Non-intrinsic viral nAChR attachment compromises integrative interneuronal communication substantially. This explains the cognitive, neuromuscular and mood impairment, as well as the vegetative symptoms, characterizing post-COVID-19 syndrome. The agonist ligand nicotine shows an up to 30-fold higher affinity to nACHRs than acetylcholine (ACh). We therefore hypothesize that this molecule could displace the virus from nAChR attachment and pave the way for unimpaired cholinergic signal transmission. Treating several individuals suffering from post-COVID-19 syndrome with a nicotine patch application, we witnessed improvements ranging from immediate and substantial to complete remission in a matter of days.

Acute worsening of CADASIL in a patient with COVID-19 infection: illustrative case.

BACKGROUND: Reports of cerebrovascular ischemia and stroke occurring as predominant neurological sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), are increasingly evident within the literature. While various pathophysiological mechanisms have been postulated, including hypercoagulability, endothelial invasion, and systemic inflammation, discrete mechanisms for viral neurotropism remain unclear and controversial. OBSERVATIONS: The authors present a unique case study of a 64-year-old male with acute COVID-19 infection and acute worsening of previously stable cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare heritable arteriopathy due to mutation in the Notch3 gene, which is critical for vascular development and tone. Delayed cranial neuropathies, brainstem fluid-attenuated inversion recovery signal, and enhancement of olfactory and vagus nerves on magnetic resonance neurography in this patient further support viral neurotropism via cranial nerves in addition to cerebral vasculature. LESSONS: To the authors' knowledge, this is the first case in the literature that not only demonstrates the consequences of COVID-19 infection in a patient with altered cerebrovascular autoregulation such as CADASIL but also highlights the tropism of SARS-CoV-2 for (1) cranial nerves as a mode of entry to the central nervous system and (2) vessels as a cause of cerebrovascular ischemia.

Neuromodulation Strategies to Reduce Inflammation and Improve Lung Complications in COVID-19 Patients.

Since the outbreak of the COVID-19 pandemic, races across academia and industry have been initiated to identify and develop disease modifying or preventative therapeutic strategies has been initiated. The primary focus has been on pharmacological treatment of the immune and respiratory system and the development of a vaccine. The hyperinflammatory state ("cytokine storm") observed in many cases of COVID-19 indicates a prognostically negative disease progression that may lead to respiratory distress, multiple organ failure, shock, and death. Many critically ill patients continue to be at risk for significant, long-lasting morbidity or mortality. The human immune and respiratory systems are heavily regulated by the central nervous system, and intervention in the signaling of these neural pathways may permit targeted therapeutic control of excessive inflammation and pulmonary bronchoconstriction. Several technologies, both invasive and non-invasive, are available and approved for clinical use, but have not been extensively studied in treatment of the cytokine storm in COVID-19 patients. This manuscript provides an overview of the role of the nervous system in inflammation and respiration, the current understanding of neuromodulatory techniques from preclinical and clinical studies and provides a rationale for testing non-invasive neuromodulation to modulate acute systemic inflammation and respiratory dysfunction caused by SARS-CoV-2 and potentially other pathogens. The authors of this manuscript have co-founded the International Consortium on Neuromodulation for COVID-19 to advocate for and support studies of these technologies in the current coronavirus pandemic.

Transcutaneous Auricular Vagus Nerve Stimulation Improves Inflammation but Does Not Interfere with Cardiac Modulation and Clinical Symptoms of Individuals with COVID-19: A Randomized Clinical Trial.

Transcranial auricular vagus nerve stimulation (taVNS) has shown effectiveness in reducing inflammation and depression. Thus, this study evaluated its effect on inflammation, cardiac autonomic modulation, and clinical symptoms in individuals affected by COVID-19. Methods: There were 52 randomized participants hospitalized with COVID-19 diagnosis who were to receive active (a-taVNS) or sham taVNS (s-taVNS) for 90 min twice a day for seven consecutive days. Interleukin 6 (IL-6), 10 (IL-10), cortisol, C-reactive protein (CRP), heart rate variability (HRV), and clinical symptoms were assessed before and after seven days of treatment. There were also seven- and fourteen-day follow-ups for clinical symptoms, including anxiety and depression levels, as well as a six-month follow-up for memory and attention levels. Results: There was significant reduction in CRP -23.9%, (95% CI -46.3 to -1.4) and IL-6 -37.7%, (95% CI -57.6 to -17.7) for the a-taVNS group. There were no changes in IL-10, cortisol levels, or in HRV results (p > 0.05) in both groups. There were no changes regarding clinical symptoms, except for a significant decrease in depression level (-2.85, 95% CI -5.44 to -0.27) in the a-taVNS group. Conclusion: taVNS showed effects on CRP, IL-6, and depression levels; however, it did not affect other clinical symptoms.

Transcutaneous Electrical Cranial-Auricular Stimulation (Tecas) for Treatment of Insomnia Disorder with Comorbid Major Depressive Disorder: A Case Series: E-Poster Viewing

Introduction: Insomnia disorder (ID) and major depressive disorder (MDD) are highly comorbid, above 80% of MDD patients have insomnia disorder. Acupuncture as a major complementary and alternative medicine (CAM) therapy, is utilized extensively in Asia to treat mental health disorders.Transcutaneous electrical cranial-auricular stimulation (TECAS) is a potential new type of acupuncture treatment for MDD and ID which combines the scalp points and auricular points most commonly used by acupuncturists. It has the advantages of portability, quantifiable stimulation parameters and comfort, especially for home treatment under the normal situation of COVID-19, which can avoid the risk of infection due to frequent hospital trips. Materials / Methods: 10 ID-MDD patients were treated by TECAS which was administered at the bilateral auricular acupoints, Bai Hui (GV-20) and Yin Tang (GV-29) (waveform:4/20 Hz, wave width: 0.2ms+/-30%) for twice a day last 8 weeks. Pittsburgh Sleep Quality Index (PSQI) and Hamilton Depression Rating Scale(HAMD) of ID-MDD patients were evaluated before and after treatment. Result(s): HAMD-17 scores of 10 patients were lower at 4 and 8 weeks than before TECAS treatment, and the reduction was greater at 4 weeks than at 8 weeks. PSQI scores of 8 patients decreased at 4 and 8 weeks compared with before treatment, and the decrease was greater in the fourth week than in the 8th week. Insomnia of 2 patients improved at 4 weeks of treatment, but became worse in the 8th week as before treatment.7 out of 10 patients showed full insomnia response (50% reduction in PSQI) and 8 patients showed full depression response (50% reduction in HAMD-17 scores). Discussion(s): We suggest TECAS is a good therapeutic strategy to modulate the vagus nerve and trigeminal nerve propagate through electrical stimulation projected by neurons from peripheral sites to the central nervous system. Furthermore, we speculate that TECAS can make the trigeminal nerve afferent fibers and vagus nerve auricular branch carry messages from head facial stimulation to NTS, locus coeruleus, raphe nucleus, medullary reticular activating system and structure of the thalamus, and then to feel, edge, cortical and subcortical structures, so the electrical stimulation subcortical can cause direct regulation, namely the change of cortical excitability. Conclusion(s): These preliminary results in this group of CID-MDD patients are encouraging and need to be replicated in prospective sham-controlled studies with larger sample sizes. In addition, for patients with insomnia and depression, it is important to consider combining TECAS with psychotherapy to avoid the interference of acute negative emergency events. Acknowledgements: The support of National Key R&D Program of China (No.2018YFC1705800) and Key Laboratory of Acupuncture and Chronobiology of Sichuan Province(No.2021004) for this project is gratefully acknowledged. Learning Objectives: 1. To provide a new non-drug method for acupuncture treatment of insomnia and depression;2. Provide preliminary experimental results for the large-sample experimental design of TECAS for the treatment of insomnia and depression;3. Compared with previous studies on insomnia and depression, the regularity and characteristics of TECAS in treating insomnia and depression were found. Keywords: Transcutaneous Electrical Cranial-Auricular Stimulation (TECAS), insomnia disorder, a case series, acupuncture, Major Depressive Disorder Copyright © 2022