Brainstem Dysfunction in SARS-COV-2 Infection can be a Potential Cause of Respiratory Distress.

BACKGROUND: A terrible pandemic, Covid-19, has captivated scientists to investigate if SARS-CoV-2 virus infects the central nervous system (CNS). A crucial question is if acute respiratory distress syndrome (ARDS), the main cause of death in this pandemic, and often refractory to treatments, can be explained by respiratory center dysfunction. OBJECTIVE: To discuss that ARDS can be caused by SARS-CoV-2 infection of the respiratory center in the brainstem. MATERIALS AND METHODS: I reviewed literature about SARS-CoV-2 mechanisms to infect the respiratory center in the brainstem. RESULTS AND CONCLUSIONS: An increasing amount of reports demonstrates that neurotropism is a common feature of coronavirus, which have been found in the brains of patients and experimental models, where the brainstem was severely infested. Recent studies have provided tremendous indication of the incidence of acute respiratory failure due to SARS-CoV-2 infection of the brainstem. SARS-CoV-2 might infect the CNS through the olfactory bulb, spreading from the olfactory nerves to the rhinencephalon, and finally reaching the brainstem. Hence, the virus infection causes respiratory center dysfunctions, leading to ARDS in COVID-19 patients. I conclude that acute ARDS in Covid-19 can be caused by SARS-CoV-2 invasion of brainstem respiratory center, suggesting the needs of more specific and aggressive treatments, with the direct participation of neurologists and neurointensivists.

Can self-relevant stimuli help assessing patients with disorders of consciousness?

Emotional and self-relevant stimuli are able to automatically attract attention and their use in patients suffering from disorders of consciousness (DOC) might help detecting otherwise hidden signs of cognition. We here recorded EEG in three Locked-in syndrome (LIS) and four Vegetative State/Unresponsive Wakefulness Syndrome (VS/UWS) patients while they listened to the voice of a family member or an unfamiliar voice during a passive. Data indicate that, in a passive listening condition, the familiar voice induces stronger alpha desynchronization than the unfamiliar one. In an active condition, the target evoked stronger alpha desynchronization in controls, two LIS patients and one VS/UWS patient. Results suggest that self-relevant familiar voice stimuli can engage additional attentional resources and might allow the detection of otherwise hidden signs of instruction-following and thus residual awareness. Further studies are necessary to find sensitive paradigms that are suited to find subtle signs of cognition and awareness in DOC patients.

Anatomic and Functional Connectivity Relationship in Autistic Children During Three Different Experimental Conditions.

A group of 21 autistic children were studied for determining the relationship between the anatomic (AC) versus functional (FC) connectivity, considering short-range and long-range brain networks. AC was assessed by the DW-MRI technique and FC by EEG coherence calculation, in three experimental conditions: basal, watching a popular cartoon with audio (V-A), and with muted audio track (VwA). For short-range connections, basal records, statistical significant correlations were found for all EEG bands in the left hemisphere, but no significant correlations were found for fast EEG frequencies in the right hemisphere. For the V-A condition, significant correlations were mainly diminished for the left hemisphere; for the right hemisphere, no significant correlations were found for the fast EEG frequency bands. For the VwA condition, significant correlations for the rapid EEG frequencies mainly disappeared for the right hemisphere. For long-range connections, basal records showed similar correlations for both hemispheres. For the right hemisphere, significant correlations incremented to all EEG bands for the V-A condition, but these significant correlations disappeared for the fast EEG frequencies in the VwA condition. It appears that in a resting-state condition, AC is better associated with functional connectivity for short-range connections in the left hemisphere. The V-A experimental condition enriches the AC and FC association for long-range connections in the right hemisphere. This might be related to an effective connectivity improvement due to full video stimulation (visual and auditory). An impaired audiovisual interaction in the right hemisphere might explain why significant correlations disappeared for the fast EEG frequencies in the VwA experimental condition.

QEEG spectral and coherence assessment of autistic children in three different experimental conditions.

We studied autistics by quantitative EEG spectral and coherence analysis during three experimental conditions: basal, watching a cartoon with audio (V-A), and with muted audio band (VwA). Significant reductions were found for the absolute power spectral density (PSD) in the central region for delta and theta, and in the posterior region for sigma and beta bands, lateralized to the right hemisphere. When comparing VwA versus the V-A in the midline regions, we found significant decrements of absolute PSD for delta, theta and alpha, and increments for the beta and gamma bands. In autistics, VwA versus V-A tended to show lower coherence values in the right hemisphere. An impairment of visual and auditory sensory integration in autistics might explain our results.

Zolpidem arousing effect in persistent vegetative state patients: autonomic, EEG and behavioral assessment.

OBJECTIVE: To study the Zolpidem arousing effect in persistent vegetative state (PVS) patients combining clinical evaluation, autonomic assessment by heart rate variability (HRV), and EEG records. METHODS: We studied a group of 8 PVS patients and other 8 healthy control subjects, matched by age and gender. The patients and controls received drug or placebo in two experimental sessions, separated by 10-14 days. The first 30 minutes of the session were considered the basal record, and then Zolpidem was administered. All participants were evaluated clinically, by EEG, and by HRV during the basal record, and for 90 minutes after drug intake. RESULTS: We found in all patients, time-related arousing signs after Zolpidem intake: behavioral (yawns and hiccups), activation of EEG cortical activity, and a vagolytic chronotropic effect without a significant increment of the vasomotor sympathetic tone. CONCLUSIONS: We demonstrated time-related arousing signs after Zolpidem intake. We discussed possible mechanisms to explain these patho-physiological findings regarding EEG cortical activation and an autonomic vagolytic drug effect. As this autonomic imbalance might induce cardiocirculatory complications, which we didn't find in any of our patients, we suggest developing future trials under control of physiological indices by bedside monitoring. However, considering that this arousing Zolpidem effect might be certainly related to brain function improvement, it should be particularly considered for the development of new neuro-rehabilitation programs in PVS cases. According to the literature review, we claim that this is the first report about the vagolitic effect of Zolpidem in PVS cases.

Zolpidem induces paradoxical metabolic and vascular changes in a patient with PVS.

INTRODUCTION: Zolpidem is a non-benzodiazepine drug used for the therapy of insomnia, which has selectivity for stimulating the effect of GABA-A receptors. Recently, a paradoxical arousing effect of zolpidem in patients with severe brain damage has been repeatedly reported. METHODS: A placebo-controlled magnetic resonance study was conducted to evaluate its effect on BOLD and metabolites spectral signals in a patient with severe brain injuries and an age-matched healthy volunteer. A multi-modal analysis was used to assess aspects in the pharmacologically-induced changes in the resting-state brain metabolism. RESULTS: A significantly increased BOLD signal was transiently localized in the left frontal cortices, bilateral anterior cingulated areas, left thalamus and right head of the caudate nucleus. The healthy subject showed a deactivation of the frontal, parietal and temporal cortices. BOLD signal changes were found to significantly correlate with concentrations of extravascular metabolites in the left frontal cortex. It is discussed that, when zolpidem attaches to modified GABA receptors of neurodormant brain cells, brain activation is induced. This might explain the significant correlations of BOLD signal changes and proton-MRS metabolites in this patient after zolpidem. CONCLUSION: It was concluded that proton-MRS and BOLD signal assessment could be used to study zolpidem-induced metabolic modulation in a resting state.

Heart rate variability for assessing comatose patients with different Glasgow Coma Scale scores.

OBJECTIVE: To assess the autonomic nervous system (ANS) in coma by heart rate variability (HRV). METHODS: Sixteen comatose patients and 22 normal subjects with comparable ages and genders were studied. Patients were classified in two subgroups according to the Glasgow Coma Scale (GCS). Time, frequency, and informational HRV domain indices were calculated. RESULTS: A notable reduction of HRV was found in patients. Regarding the time domain indices, the triangular index, and the Delta_RRs, were significantly reduced in the subgroup with GCS=3. Absolute power for the whole frequency spectrum decreased whenever GCS scores were lower. A significant decrement was found for absolute power of the VLF and LF bands in the subgroup of GCS=3, and although it was lower for the HF band in these patients, those changes were not statistically significantly different. The LF/HF ratio and the Shannon´s entropy indices were significantly reduced in the subgroup with GCS=3. Our results are discussed regarding the progressive dysfunction the ANS networks when coma deepens. CONCLUSIONS: The HRV procedure is a powerful tool to assess the ANS in comatose patients. SIGNIFICANCE: HRV is a minimally invasive, low-cost methodology, suitable for assessing the ANS in coma.

Vegetative state is a pejorative term.

The term persistent vegetative state (PVS) refers to the only circumstance in which an apparent dissociation of both components of consciousness is found, characterized by preservation of wakefulness with an apparent loss of awareness. Several authors have recently demonstrated by functional neuroimaging studies that a small subset of unresponsive "vegetative" patients may show unambiguous signs of consciousness and command following that is inaccessible to clinical examination at the bedside. The term "estado vegetativo" used in Spanish to describe the PVS syndrome by physicians came from the English-Spanish translation. The Spanish term "vegetativo" is related to unconscious vital functions, and "vegetal" is relative to plants. According to our experience, when a physician informs to patients' relatives that his/her family member's diagnosis is a "estado vegetativo", they understand the he/she is no more a human being, that there is no hope of recovery. The European Task Force on Disorders of Consciousness has recently proposed a new term, unresponsive wakefulness syndrome (UWS), to assist society in avoiding the depreciatory term vegetative state. Our group has embraced the use of the new term UWS and might suggest that we change our concept and use of the term MCS to minimally responsive wakefulness state (MRWS), or minimally aware wakefulness state (MAWS). Medical terms must be current and avoid any pejorative description of patients, which will promote our abilities to serve humankind and challenge neuroscientists to offer society new and realistic hopes for neurorehabilitation.

TCD diastolic velocity decay and pulsatility index increment in PVS cases.

BACKGROUND: Functional neuroimaging has provided new insights for assessing cerebral function in persistent vegetative state patients (PVS). Compared to controls, positron emission tomography and single photon emission tomography have shown a substantial reduction of global brain cerebral glucose metabolism and perfusion in PVS. Doppler ultrasonography (TCD) assesses local blood flow velocity and direction in the proximal portions of large intracranial arteries; it is a noninvasive technique, and it can be carried out at the bedside. To date, few studies have applied TCD to study PVS. METHODS: We assessed intracranial circulation by TCD in five PVS patients. The cause of brain insult was hypoxic encephalopathy in four cases, and the other suffered an embolic cerebral infarct causing a top of the basilar artery syndrome. The sample volume was set at 12 mm; power output and gain settings were maximized as needed. The temporal bone acoustic window was not suitable for intracranial vessel insonation in all patients. As an alternative, the internal carotid artery siphon was assessed by orbital insonation between 55-70 mm. RESULTS: Systolic velocity was within a normal range, between 44 and 62 cm/second in all cases. However, the diastolic amplitude was reduced, as well as the end diastolic velocity, and the pulsatility index was increased in all patients. CONCLUSIONS: We conclude that TCD diastolic velocity decrement and PI augmentation in our cases might be related to uncoupling of cerebral blood flow and cerebral metabolic rate, arising from reduced cerebral glucose consumption and oxygen uptake, after extensive brain injury.