Young people diagnosed with COVID-19 have problems with their nervous system when compared with healthy control subjects

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New research published in the Journal of Physiology found that otherwise healthy young people diagnosed with COVID-19, regardless of their symptom severity, have problems with their nervous system when compared with healthy control subjects.

Specifically, the system that oversees the fight-or-flight response, the sympathetic nervous system, seems to be abnormal (overactive in some instances and underactive in others) in those recently diagnosed with COVID-19.

These results are especially important given the emerging evidence of symptoms like racing hearts being reported in conjunction with “long-COVID.”

The impact of this alteration in fight-or-flight response, especially if prolonged, means that many processes within the body could be disrupted or affected.

This research team has specifically been looking at the impact on the cardiovascular system – including blood pressure and blood flow – but the sympathetic nervous system is also important in exercise responses, the digestive system, the immune function, and more.

Understanding what happens in the body shortly following diagnosis of COVID-19 is an important first step towards understanding the potential long-term consequences of contracting the disease.

Importantly, if similar disruption of the flight-or-fight response, like that found here in young individuals, is present in older adults following COVID-19 infection, there may be substantial adverse implications for cardiovascular health.

The researchers studied lung function, exercise capacity, vascular function, and neural cardiovascular control (the control of heartbeat by the brain).

They used a technique called microneurography, wherein the researchers inserted a tiny needle with an electrode into a nerve behind the knee, which records the electrical impulses of that nerve and measures how many bursts of electrical activity are happening and how big the bursts are.

From this nerve activity, they can assess the function of the sympathetic nervous system through a series of tests. For all the tests, the subject was lying on their back on a bed. First, the researchers looked at the baseline resting activity of the nerves, heart rate, and blood pressure.

Resting sympathetic nerve activity was higher in the COVID-19 participants than healthy people used as controls in the experiment.

Then, the subject did a “cold pressor test,” where they stick their hand in an ice-water mixture (~0° C) for two minutes. In healthy individuals, this causes a profound increase in that sympathetic nerve (fight-or-flight) activity and blood pressure. The COVID-19 subjects rated their pain substantially lower than healthy subjects typically do.

Finally, the participant was moved to an upright position (the bed they’re lying on can tilt up and down) to see how well their body can respond to a change in position. The COVID-19 subjects had a pretty large increase in heart rate during this test; they also had higher sympathetic nerve activity throughout the tilt test compared with other healthy young adults.

As with all research on humans, there are limitations to this study. However, the biggest limitation in the present study is its cross-sectional nature – in other words, we do not know what the COVID-19 subjects’ nervous system activity “looked like” before they were diagnosed with COVID-19.

These findings are consistent with the increasing reports of long-COVID symptoms pertaining to problems with the fight-or-flight response.

Abigail Stickford, senior author on this study said, “Through our collaborative project, we have been following this cohort of COVID-19 subjects for six months following their positive test results. This work was representative of short-term data, so the next steps for us are to wrap up data collection and interpret how the subjects have changed over this time.”

Specifically, the system that oversees the fight-or-flight response, the sympathetic nervous system, seems to be abnormal (overactive in some instances and underactive in others) in those recently diagnosed with COVID-19.

These results are especially important given the emerging evidence of symptoms like racing hearts being reported in conjunction with “long-COVID.”

The impact of this alteration in fight-or-flight response, especially if prolonged, means that many processes within the body could be disrupted or affected.

This research team has specifically been looking at the impact on the cardiovascular system – including blood pressure and blood flow – but the sympathetic nervous system is also important in exercise responses, the digestive system, the immune function, and more.

Understanding what happens in the body shortly following diagnosis of COVID-19 is an important first step towards understanding the potential long-term consequences of contracting the disease.

Importantly, if similar disruption of the flight-or-fight response, like that found here in young individuals, is present in older adults following COVID-19 infection, there may be substantial adverse implications for cardiovascular health.

The researchers studied lung function, exercise capacity, vascular function, and neural cardiovascular control (the control of heartbeat by the brain).

They used a technique called microneurography, wherein the researchers inserted a tiny needle with an electrode into a nerve behind the knee, which records the electrical impulses of that nerve and measures how many bursts of electrical activity are happening and how big the bursts are.

From this nerve activity, they can assess the function of the sympathetic nervous system through a series of tests. For all the tests, the subject was lying on their back on a bed. First, the researchers looked at the baseline resting activity of the nerves, heart rate, and blood pressure. Resting sympathetic nerve activity was higher in the COVID-19 participants than healthy people used as controls in the experiment.

Then, the subject did a “cold pressor test,” where they stick their hand in an ice-water mixture (~0° C) for two minutes. In healthy individuals, this causes a profound increase in that sympathetic nerve (fight-or-flight) activity and blood pressure. The COVID-19 subjects rated their pain substantially lower than healthy subjects typically do.

Finally, the participant was moved to an upright position (the bed they’re lying on can tilt up and down) to see how well their body can respond to a change in position.

The COVID-19 subjects had a pretty large increase in heart rate during this test; they also had higher sympathetic nerve activity throughout the tilt test compared with other healthy young adults.

As with all research on humans, there are limitations to this study. However, the biggest limitation in the present study is its cross-sectional nature—in other words, we do not know what the COVID-19 subjects’ nervous system activity “looked like” before they were diagnosed with COVID-19.

These findings are consistent with the increasing reports of long-COVID symptoms pertaining to problems with the fight-or-flight response.

Abigail Stickford, senior author on this study said, “Through our collaborative project, we have been following this cohort of COVID-19 subjects for six months following their positive test results. This work was representative of short-term data, so the next steps for us are to wrap up data collection and interpret how the subjects have changed over this time.”


The coronavirus infectious disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, was initially recognized as a respiratory tract disease which could lead to an acute respiratory distress syndrome. However, there is growing evidence of a multi-organ involvement (Gupta et al., 2020).

Several authors reported central nervous system (CNS) manifestations, as anosmia referring to olfactory tract involvement. Other critical presentations, including meningoencephalitis, seizures, status epilepticus (SE), encephalopathy, and altered mental status were also described (Ellul et al., 2020).

Neurological complications, such as encephalopathy and seizures/SE, and electroencephalographic (EEG) abnormalities, mainly diffuse slowing and epileptiform discharges, have already been described in past viral pandemics such as influenza A H1N1 (Ekstrand et al., 2010; Kedia et al., 2011; Ibrahim and Haddad, 2014). Results of EEG in patients with COVID-19 were increasingly reported. While the volume of COVID-19-related case studies is still growing, we present the spectrum of EEG findings published at the moment, allowing physicians to be cognizant of this new and emerging literature while dealing with COVID-19 patients.

Discussion

The vast majority of these studies emphasized the absence of specificity of EEG abnormalities reported in COVID-19 patients, as generalized slowing of the background activity, focal slowing sometimes associated with sharp waves, seizures, SE, and predictable pattern of metabolic/toxic or postanoxic encephalopathy in ICU patients. Numerous EEGs in the context of COVID-19 were recorded in elderly patients and mainly in male patients, with multiple comorbidities especially chronic brain disorders, under various psychotropic drugs or in critically ill conditions. C

onfounding factors such as infections, metabolic disturbances, severe hypoxemia, hyperthermia, and psychotropic drugs (such as antiepileptic or sedative drugs) were frequent at the time of EEG recordings. All these confounding factors may contribute to the modification of brain activity and therefore EEG findings. Thus, based on the current literature, it seems not possible to identify a specific EEG pattern due to the suspected neuroinvasion of SARS-CoV-2 in patients who displayed neurological manifestations of COVID-19.

Most current studies with available EEG data are case reports or retrospective single-center series. All reported patients are very heterogeneous concerning prior neurological histories, illness severity, and use of psychotropic drugs. Moreover, some studies reported EEG recorded with limited montage and number of electrodes that may limit the detection of EEG abnormalities. EEG is not a systematic exam in the diagnostic workup of COVID-19 patients.

All patients reported in the current literature had an EEG for an urgent clinical indication due to concerning neurological symptoms. A wider neurological multimodality screening, including EEG, of COVID-19 patients may be suggested to grow the body of knowledge on the SARS-CoV-2 infection. However, it will face many logistic difficulties and ethical and safety concerns regarding the availability of trained personnel to EEG recordings and the risk of contamination with the SARS-CoV-2.

It should be pointed out that many EEG abnormalities reported were recorded over anterior or frontal regions. Regardless of EEG montage used by clinicians and neurophysiologists, it thus seems essential to include frontal electrodes. Periodicity, morphology, and reactivity of these frontal abnormalities were not mentioned in all studies. Moreover, a few reported periodic patterns, as GPDs (Ayub et al., 2020; Beach et al., 2020; Delorme et al., 2020; Louis et al., 2020; Pellinen et al., 2020; Petrescu et al., 2020), GPDs with bifrontal predominance (Galanopoulou et al., 2020; Vellieux et al., 2020; Vespignani et al., 2020), and LPDs (Conte et al., 2020; Le Guennec et al., 2020; Pellinen et al., 2020; Petrescu et al., 2020; Vespignani et al., 2020; Young et al., 2020).

In particular, these frontal periodic discharges were monomorphic and displayed a short interval, and the absence of reactivity was noted (Vellieux et al., 2020; Vespignani et al., 2020). These frontal periodic discharges may indicate an acute neurological process linked to the brain SARS-CoV-2 infection.

In COVID-19 patients, the combination of the frontal localization of these EEG discharges, the frequently reported anosmia (Yazdanpanah et al., 2020), the olfactory bulb abnormalities found on brain imaging (Lin et al., 2020), and the hypometabolism within the orbitofrontal cortex on functional brain imaging (Karimi-Galougahi et al., 2020) may support the hypothesis whereby SARS-CoV-2 could invade the brain through the olfactory pathway. Then, it could spread transneuronally to other related brain areas particularly to frontal lobes, especially the orbital prefrontal cortex, which are adjacent to olfactory structures (Huang J. et al., 2020).

Conclusion

In the context of the SARS-CoV-2 infection, increasing EEG results were published along with clinical reports describing various neurological symptoms in patients with COVID-19. Due to the suspected neuroinvasion of SARS-CoV-2, the major issue when interpreting EEG is to determine whether the observed abnormalities reflect this viral neuroinvasion, a severe encephalopathy with systemic and brain inflammation, hypoxemia and hyperthermia, and/or many confounding factors especially due to critical illness. At this time, no study had described specific EEG abnormalities of the SARS-CoV-2 infection.

The majority of currently reported EEGs showed generalized slowing, focal slowing, epileptiform discharges with seizures, and SE. However, frontal discharges, for some periodic, may integrate in the olfactory hypothesis of the CNS invasion of SARS-CoV-2. It reinforces the need to accumulate precise neurophysiological observations of COVID-19 patients worldwide and to aggregate multimodality screening of these patients also with clinical, radiological, biological, and neuropathological data.

reference link : https://www.frontiersin.org/articles/10.3389/fphys.2020.622466/full


Original Research: “COVID‐19 is getting on our nerves: Sympathetic neural activity and hemodynamics in young adults recovering from SARS‐CoV‐2” by Nina L. Stute et al. Journal of Physiology

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