Exercise-induced potentiation of the acute hypoxic ventilatory response: Neural mechanisms and implications for cerebral blood flow.

A given dose of hypoxia causes a greater increase in pulmonary ventilation during physical exercise than during rest, representing an exercise-induced potentiation of the acute hypoxic ventilatory response (HVR). This phenomenon occurs independently from hypoxic blood entering the contracting skeletal muscle circulation or metabolic byproducts leaving skeletal muscles, supporting the contention that neural mechanisms per se can mediate the HVR when humoral mechanisms are not at play. However, multiple neural mechanisms might be interacting intricately. First, we discuss the neural mechanisms involved in the ventilatory response to hypoxic exercise and their potential interactions. Current evidence does not support an interaction between the carotid chemoreflex and central command. In contrast, findings from some studies support synergistic interactions between the carotid chemoreflex and the muscle mechano- and metaboreflexes. Second, we propose hypotheses about potential mechanisms underlying neural interactions, including spatial and temporal summation of afferent signals into the medulla, short-term potentiation and sympathetically induced activation of the carotid chemoreceptors. Lastly, we ponder how exercise-induced potentiation of the HVR results in hyperventilation-induced hypocapnia, which influences cerebral blood flow regulation, with multifaceted potential consequences, including deleterious (increased central fatigue and impaired cognitive performance), inert (unchanged exercise) and beneficial effects (protection against excessive cerebral perfusion).

Hemodynamic changes in the temporalis and masseter muscles during acute stress in healthy humans.

PURPOSE: Autonomic control of orofacial areas is an integral part of the stress response, controlling functions such as pupil dilatation, salivation, and skin blood flow. However, the specific control of blood flow in head muscles during stress is unknown. This study aims to investigate the hemodynamic response of temporalis and masseter muscles in response to five different stressors. METHODS: Sixteen healthy individuals were subjected to a randomized series of stressors, including cold pressor test, mental arithmetic test, apnea, isometric handgrip, and post-handgrip muscle ischemia, while in the sitting posture. Finger-pulse photoplethysmography was used to measure arterial blood pressure, heart rate, and cardiac output. Near-infrared spectroscopy was used to measure changes in tissue oxygenation and hemoglobin indices from the temporalis and masseter muscles. RESULTS: All stressors effectively and significantly increased arterial blood pressure. Tissue oxygenation index significantly increased in both investigated head muscles during mental arithmetic test (temporalis: 4.22 ± 3.52%; masseter: 3.43 ± 3.63%) and isometric handgrip (temporalis: 3.45 ± 3.09%; masseter: 3.26 ± 3.07%), suggesting increased muscle blood flow. Neither the masseter nor the temporalis muscles evidenced a vasoconstrictive response to any of the stressors tested. CONCLUSION: In the different conditions, temporalis and masseter muscles exhibited similar hemodynamic patterns of response, which do not include the marked vasoconstriction generally observed in limb muscles. The peculiar sympathetic control of head muscles is possibly related to the involvement of these muscles in aggressive/defensive reactions and/or to their unfavorable position with regard to hydrostatic blood levels.

Hemodynamic monitoring in the human temporalis muscle using near-infrared spectroscopy.

Objective. Altered temporal muscle perfusion is implicated in several painful disorders afflicting orofacial and head regions, including temporomandibular joint dysfunctions, bruxism, and headache. Knowledge about the regulation of blood supply to the temporalis muscle is limited, due to methodological difficulties. The study aimed to test the feasibility of near-infrared spectroscopy (NIRS) monitoring of the human temporal muscle.Approach. Twenty-four healthy subjects were monitored with a 2-channel NIRS: amuscleprobe placed over the temporal muscle and abrainprobe placed on the forehead. A series of teeth clenching at 25, 50, and 75% of maximum voluntary contraction for 20 s and hyperventilation for 90 s at 20 mmHg of end-tidal CO2were performed, to elicit hemodynamic changes in muscle and brain, respectively.Main results. In twenty responsive subjects, NIRS signals from both probes were consistently different during both tasks. The absolute change in tissue oxygenation index (ΔTOI) as detected by muscle and brain probes was -9.40 ± 12.28 and 0.29 ± 1.54% during teeth clenching (p< 0.01) at 50% maximum voluntary contraction, while -1.03 ± 2.70 and -5.11 ± 3.81% during hyperventilation (p< 0.01), respectively.Significance. Distinct response patterns were observed from the temporal muscle and prefrontal cortex which proves that this technique is adequate to monitor tissue oxygenation and hemodynamic changes in human temporal muscle. Noninvasive and reliable monitoring of hemodynamics in this muscle will help to extend basic and clinical investigations about the peculiar control of blood flow in head muscles.

Ventilatory response to peripheral chemoreflex and muscle metaboreflex during static handgrip in healthy humans: evidence of hyperadditive integration.

NEW FINDINGS: What is the central question of this study? What is the effect of peripheral chemoreflex and muscle metaboreflex integration on ventilation regulation, and what is the effect of integration on breathing-related sensations and emotions? What is the main finding and its importance? Peripheral chemoreflex and muscle metaboreflex coactivation during isocapnic static handgrip exercise appeared to elicit a hyperadditive effect with regard to ventilation and an additive effect with regard to breathing-related sensations and emotions. These findings reveal the nature of the integration between two neural mechanisms that operate during small-muscle static exercise performed under hypoxia. ABSTRACT: Exercise augments the hypoxia-induced ventilatory response in an exercise intensity-dependent manner. A mutual influence of hypoxia-induced peripheral chemoreflex activation and exercise-induced muscle metaboreflex activation might mediate the augmentation phenomenon. However, the nature of these reflexes' integration (i.e., hyperadditive, additive or hypoadditive) remains unclear, and the coactivation effect on breathing-related sensations and emotions has not been explored. Accordingly, we investigated the effect of peripheral chemoreflex and muscle metaboreflex coactivation on ventilatory variables and breathing-related sensations and emotions during exercise. Fourteen healthy adults performed 2-min isocapnic static handgrip, first with the non-dominant hand and immediately after with the dominant hand. During the dominant hand exercise, we (a) did not manipulate either reflex (control); (b) activated the peripheral chemoreflex by hypoxia; (c) activated the muscle metaboreflex in the non-dominant arm by post-exercise circulatory occlusion (PECO); or (d) coactivated both reflexes by simultaneous hypoxia and PECO use. Ventilation response to coactivation of reflexes (mean ± SD, 13 ± 6 l/min) was greater than the sum of responses to separated activations of reflexes (mean ± SD, 8 ± 8 l/min, P = 0.005). Breathing-related sensory and emotional responses were similar between coactivation of reflexes and the sum of separate activations of reflexes. Thus, the peripheral chemoreflex and muscle metaboreflex integration during exercise appeared to be hyperadditive with regard to ventilation and additive with regard to breathing-related sensations and emotions in healthy adults.

Results of Numerical Modeling of Blood Flow in the Internal Jugular Vein Exhibiting Different Types of Strictures.

The clinical relevance of nozzle-like strictures in upper parts of the internal jugular veins remains unclear. This study was aimed at understanding flow disturbances caused by such stenoses. Computational fluid dynamics software, COMSOL Multiphysics, was used. Two-dimensional computational domain involved stenosis at the beginning of modeled veins, and a flexible valve downstream. The material of the venous valve was considered to be hyperelastic. In the vein models with symmetric 2-leaflets valve without upstream stenosis or with minor 30% stenosis, the flow was undisturbed. In the case of major 60% and 75% upstream stenosis, centerline velocity was positioned asymmetrically, and areas of reverse flow and flow separation developed. In the 2-leaflet models with major stenosis, vortices evoking flow asymmetry were present for the entire course of the model, while the valve leaflets were distorted by asymmetric flow. Our computational fluid dynamics modeling suggests that an impaired outflow from the brain through the internal jugular veins is likely to be primarily caused by pathological strictures in their upper parts. In addition, the jugular valve pathology can be exacerbated by strictures located in the upper segments of these veins.

Novel Eco-Friendly Stability Indicating Capillary Zone Electrophoresis Method for Determination of Aripiprazole in Tablet Dosage form: DoE Directed Optimization, Development and Method Validation.

In this work, a novel environment-friendly stability indicating capillary zone electrophoresis (CZE) method has been developed and validated for assaying the aripiprazole (ARP) in tablet dosage form. The separation of ARP from its degradation products and internal standard was achieved using a fused silica capillary column (30.2 cm x 75 µm ID), a background electrolyte containing 6 mmol L-1 ammonium formate buffer (pH 3) with 5% methanol under a potential of 15 kV and detection at 214 nm. The stability indicating ability of the method was investigated by analyzing ARP after being subjected to acidic, alkaline, thermal, photolytic, and oxidative stress conditions, according to ICH guidelines. Design of experiments was used during forced degradation and method optimization. Oxidation was the main degradation pathway among those evaluated. The drug was separated from its oxidative degradation products in less than 4 min. CZE method was linear between 60 - 140 µg mL-1, R2 = 0.9980, precise (intra-day 0.88% and inter-day 1.30%). The average recovery was 100.93 ± 0.77%. This is the first method in the literature for quantification of ARP in the presence of its related degradation products with high separation efficiency, low operation cost and minimum solvent consumption. This method could be helpful in the routine quality control analysis in the pharmaceutical industries with least harmful effect on the environment. CZE is considered an eco-friendly alternative of conventionally HPLC methods.

Cerebrovascular reactivity during visual stimulation: Does hypnotizability matter?

Hypnotizability is a trait associated with several physiological correlates including cardiovascular control. The present study aimed to investigate the posterior cerebral artery flow velocity (PCAv) in basal closed eyes (B) and during visual stimulation (VS) conditions in med-highs and med-lows. Twenty-four healthy volunteers were submitted to the hypnotic assessment through the Stanford Hypnotic Susceptibility Scale, form A which classified 13 low-to-medium (med-lows) and 10 high-to-medium (med-highs) hypnotizable participants. One subject scoring 6 out of 12 was excluded from the comparisons between groups. Arterial blood pressure, heart rate, and partial pressure of end-tidal CO2 were monitored during both B and VS conditions. Simultaneously, PCAv was assessed by transcranial Doppler. Cerebrovascular Reactivity (CVR) was computed as a percentage of the PCAv change occurring during VS with respect to B (ΔPCAv). During VS both groups increased their PCAv (mean ± SD: 7.9 ± 5.2 %) significantly with no significant group difference. However, among med-highs, CVR was negatively correlated with hypnotizability scores. Thus, higher hypnotizability may be associated with lower metabolic demand in response to VS only within med-highs hypnotizable participants.

Does hypnotizability affect neurovascular coupling during cognitive tasks?

Susceptibility to hypnosis is a very pervasive psychophysiological trait characterized by different attentional abilities, information processing, and cardiovascular control. Since near infrared spectroscopy is a good index of neurovascular coupling, we used it during mental computation (MC) and trail making task (TMT) in 13 healthy low-to-medium (med-lows) and 10 healthy medium-to-high (med-highs) hypnotizable participants classified according to the Stanford Hypnotic Susceptibility Scale, form A, and characterized for the level of proneness to be deeply absorbed in related experiences by the Tellegen Absorption Scale. The med-highs reported greater absorption than med-lows. The tissue hemoglobin index (THI) and the tissue oxygenation index (TOI) increased across the tasks only in med-highs who displayed also different time courses of THI and TOI during MC and TMT, which indicates different tasks processing despite the two groups' similar performance. The findings suggest that med-highs' tissue oxygenation is more finely adjusted to metabolic demands than med-lows'.

Differential control of blood flow in masseter and biceps brachii muscles during stress.

OBJECTIVE: The present study aimed to compare sympathetic hemodynamic effects in masticatory and limb muscles in response to different stressors. DESIGN: Twelve healthy participants were subjected to a randomized series of stressors, including cold pressor test (CPT), mental arithmetic test, apnea, isometric handgrip (IHG) and post-handgrip muscle ischemia (PHGMI), while in the supine position. Spatially-resolved near-infrared spectroscopy was used to measure relative changes in blood volume and oxygenation (TOI) of the resting masseter and biceps muscles. Cardiac output, heart rate, and arterial blood pressure (ABP) were also monitored. RESULTS: Except apnea, all tests increased ABP. Different response patterns were observed in the 2 muscles: TOI significantly increased during contralateral IHG (1.24 ± 1.17%) but markedly decreased during CPT (-4.84 ± 4.09%) and PHGMI (-6.65 ± 5.31%) in the biceps muscle, while exhibiting consistent increases in the masseter (1.88 ± 1.85%; 1.60 ± 1.75%; 1.06 ± 3.29%, respectively) (p < 0.05). CONCLUSIONS: The results allow us to infer differential control of blood flow in head and limb muscles. In general, the masseter appears more prone to dilatation than the biceps, exhibiting opposite changes in response to painful stimuli (CPT and PHGMI). Several mechanisms may mediate this effect, including reduced sympathetic outflow to the extracranial vasculature of the head, generally exposed to lower hydrostatic loads than the rest of the body.

Cerebral Blood Flow in Healthy Subjects with Different Hypnotizability Scores.

Hypnotizability is a cognitive trait associated with differences in the brachial artery flow-mediated dilatation of individuals with high hypnotizability (highs) and low hypnotizability scores (lows). The study investigated possible hypnotizability-related cerebrovascular differences. Among 24 healthy volunteers, the Stanford Hypnotic Susceptibility Scale Form A identified 13 medium-to-lows (med-lows), 11 medium-to-highs (med-highs), and 1 medium hypnotizable. Hypnotizability did not influence the significant changes produced by the trail making task (TMT), mental arithmetic task (MAT), hyperventilation (HVT), and rebreathing (RBT) on heart rate (HR), arterial blood pressure (ABP), and partial pressure of end-tidal CO2 (PETCO2), but moderated the correlations between the changes occurring during tasks with respect to basal conditions (Δ) in ABP and PETCO2 with middle cerebral artery flow velocity (MCAv). In HVT, med-lows exhibited a significant correlation between ΔMCAv and ΔPETCO2, and med-highs showed a significant correlation between ΔABP and ΔMCAv. Cerebrovascular reactivity (CVR) and conductance (ΔCVCi) were significantly correlated with ΔMCAv only in med-lows during HVT and RBT. For the first time, cerebrovascular reactivity related to hypnotizability was investigated, evidencing different correlations among hemodynamic variables in med-highs and med-lows.

COVID-19-associated meningoencephalitis complicated with intracranial hemorrhage: a case report.

The coronavirus pandemic that started in December 2019 is mainly related to clinical pictures consistent with respiratory symptoms; nevertheless, reports about neurological complications have recently appeared in the medical literature. We describe a case of a 36-year-old coronavirus-positive patient that was admitted on emergency basis; his clinical presentation included neurological symptoms such as drowsiness and mild confusion. Imaging revealed findings consistent with meningoencephalitis complicated by intracerebral hematoma and subdural hematoma. The latter was surgically evacuated after it became chronic and evidence of coronavirus was found in the fluid. Our experience confirms that neurological complications might be a likely event in COVID-19. Although uncommon, the possible occurrence of meningoencephalitis should be kept in mind by physicians involved in the management of COVID-19 patients. Early recognition of brain involvement may provide better prognosis, preventing evolution into intracerebral hemorrhagic events.

Solitary bone plasmacytoma: the unusual case of extra-cranial mini brain.

Solitary plasmacytoma is an uncommon tumor. We present a case in an unusually young patient demonstrating the mini brain sign that has been published in a couple of reports as a diagnostic radiological pattern produced by plasmacytoma. Identification of "mini brain appearance" on imaging can direct the radiologist and clinicians to the diagnosis of plasmacytoma and obviate the necessity of pre-operative biopsy.

Serum glial fibrillary acidic protein is related to focal brain injury and outcome after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (aSAH) stands out from other subtypes of stroke because of the high early mortality and the risk of complications. Serum glial fibrillary acidic protein (s-GFAP) concentrations are increased after stroke. The aim of this study was to investigate whether s-GFAP could be used as a marker of brain damage and outcome after aSAH. METHODS: Serum samples were obtained on a regular basis from 116 adults during a 2-week period after aSAH and analyzed using an enzyme-linked immunosorbent assay. The World Federation of Neurological Surgeons scale was used for neurological evaluation. Outcome was assessed after 1 year and categorized according to the Extended Glasgow Outcome Scale. RESULTS: Increased s-GFAP levels were seen in 81 of the 116 patients. Maximum s-GFAP correlated with World Federation of Neurological Surgeons scale on arrival and on days 10 to 15 (r=0.37, P<0.001 and r=0.47, P<0.001, respectively). Furthermore, maximum s-GFAP levels were increased in the patient group with radiological signs of focal lesions acute or at 1 year, compared with the group without focal lesions (P<0.001 in both comparisons). Patients with secondary events (re-bleeding or ischemia) reached maximum levels later in the series and both maximum and final s-GFAP levels increased compared with the levels in patients without secondary events (P<0.001 in all 3 comparisons). Finally, maximum s-GFAP correlated with outcome (r=-0.48, P<0.001) and s-GFAP was an independent predictor of dichotomized outcome. CONCLUSIONS: s-GFAP provides information about brain injury severity and outcome after aSAH, which can be useful as a complement to clinical data.