Near-Infrared II Photobiomodulation Preconditioning Ameliorates Stroke Injury via Phosphorylation of eNOS.

BACKGROUND: The current management of patients with stroke with intravenous thrombolysis and endovascular thrombectomy is effective only when it is timely performed on an appropriately selected but minor fraction of patients. The development of novel adjunctive therapy is highly desired to reduce morbidity and mortality with stroke. Since endothelial dysfunction is implicated in the pathogenesis of stroke and is featured with suppressed endothelial nitric oxide synthase (eNOS) with concomitant nitric oxide deficiency, restoring endothelial nitric oxide represents a promising approach to treating stroke injury. METHODS: This is a preclinical proof-of-concept study to determine the therapeutic effect of transcranial treatment with a low-power near-infrared laser in a mouse model of ischemic stroke. The laser treatment was performed before the middle cerebral artery occlusion with a filament. To determine the involvement of eNOS phosphorylation, unphosphorylatable eNOS S1176A knock-in mice were used. Each measurement was analyzed by a 2-way ANOVA to assess the effect of the treatment on cerebral blood flow with laser Doppler flowmetry, eNOS phosphorylation by immunoblot analysis, and stroke outcomes by infarct volumes and neurological deficits. RESULTS: Pretreatment with a 1064-nm laser at an irradiance of 50 mW/cm2 improved cerebral blood flow, eNOS phosphorylation, and stroke outcomes. CONCLUSIONS: Near-infrared II photobiomodulation could offer a noninvasive and low-risk adjunctive therapy for stroke injury. This new modality using a physical parameter merits further consideration to develop innovative therapies to prevent and treat a wide array of cardiovascular diseases.

Intracranial dynamics biomarkers at traumatic cerebral vasospasm.

Introduction: Patients who suffer severe traumatic brain injury (sTBI) and cerebral vasospasm (CVS) frequently have posttraumatic cerebral ischemia (PCI). The research question: was to study changes in cerebral microcirculatory bed parameters in sTBI patients with CVS and with or without PCI. Material and methods: A total of 136 severe TBI patients were recruited in the study. All patients underwent perfusion computed tomography, intracranial pressure monitoring, and transcranial Doppler. The levels of cerebrovascular resistance (CVR), cerebral arterial compliance (CAC), cerebrovascular time constant (CTC), and critical closing pressure (CCP) were measured using the neuromonitoring complex. Statistical analysis was performed using parametric and nonparametric methods and factor analysis. The patients were dichotomized into PCI-positive (n = 114) and PCI-negative (n = 22) groups. Data are presented as mean values (standard deviations). Results: CVR was significantly increased, whereas CAC, CTC, and CCP were significantly decreased in sTBI patients with CVS and PCI development (p < 0.05). Factor analyses revealed that all studied microcirculatory bed parameters were significantly associated with the development of PCI (p < 0.05). Discussion and conclusion: The changes in all studied microcirculatory bed parameters in TBI patients with CVS were significantly associated with PCI development, which enables us to regard them as the biomarkers of CVS and PCI development. The causes of the described microcirculatory bed parameters changes might include complex (cytotoxic and vasogenic) brain edema development, regional microvascular spasm, and dysfunction of pericytes. A further prospective study is warranted.

Arteriovenous cerebral blood flow correlation in moderate-to-severe traumatic brain injury: CT perfusion study.

Introduction: The relationship between arterial and venous blood flow in moderate-to-severe traumatic brain injury (TBI) is poorly understood. The research question: was to compare differences in perfusion computed tomography (PCT)-derived arterial and venous cerebral blood flow (CBF) in moderate-to-severe TBI as an indication of changes in cerebral venous outflow patterns referenced to arterial inflow. Material and methods: Moderate-to-severe TBI patients (women 53; men 74) underwent PCT and were stratified into 3 groups: I (moderate TBI), II (diffuse severe TBI without surgery), and III (severe TBI after the surgery). Arterial and venous CBF were measured by PCT in both the internal carotid arteries (CBFica) and the confluence of upper sagittal, transverse, and straight sinuses (CBFcs). Results: In group I, CBFica on the left and right sides were significantly correlated with each other (p < 0.0001) and with CBFcs (p = 0.048). In group II, CBFica on the left and right sides were also correlated (P < 0.0000001) but not with CBFcs. Intracranial pressure reactivity (PRx) and CBFcs were correlated (p = 0.00014). In group III, CBFica on the side of the removed hematoma was not significantly different from the opposite CBFica (P = 0.680) and was not correlated with CBFcs. Discussion and conclusion: The increasing severity of TBI is accompanied by a rising uncoupling between the arterial and venous CBF in the supratentorial vessels suggesting a shifting of cerebral venous outflow.

Dynamics of Intracranial Pressure and Cerebrovascular Reactivity During Intrahospital Transportation of Traumatic Brain Injury Patients in Coma.

BACKGROUND: Intrahospital transportation (IHT) of patients with traumatic brain injury (TBI) is common and may have adverse consequences, incurring inherent risks. The data on the frequency and severity of clinical complications linked with IHT are contradictory, and there is no agreement on whether it is safe or potentially challenging for neurocritical care unit patients. Continuous intracranial pressure (ICP) monitoring is essential in neurointensive care. The role of ICP monitoring and management of cerebral autoregulation impairments in IHT of patients with severe TBI is underinvestigated. The purpose of this nonrandomized retrospective single-center study was to assess the dynamics of ICP and an improved pressure reactivity index (iPRx) as a measure of autoregulation during IHT. METHODS: Seventy-seven men and fourteen women with severe TBI admitted in 2012-2022 with a mean age of 33.2 ± 5.2 years were studied. ICP and arterial pressure were invasively monitored, and cerebral perfusion pressure and iPRx were calculated from the measured parameters. All patients were subjected to dynamic helical computed tomography angiography using a 64-slice scanner Philips Ingenuity computed tomography scan 1-2 days after TBI. Statistical analysis of all results was done using a paired t-test, and p was preset at < 0.05. The logistic regression analysis was performed for cerebral ischemia development dependent on intracranial hypertension and cerebrovascular reactivity. RESULTS: IHT led to an increase in ICP in all the patients, especially during vertical movement in an elevator (maximum 75.2 mm Hg). During the horizontal transportation on the floor, ICP remained increased (p < 0.05). The mean ICP during IHT was significantly higher (26.1 ± 13.5 mm Hg, p < 0.001) than that before the IHT (19.9 ± 5.3 mm Hg). The mean iPRx after and before IHT was 0.52 ± 0.04 and 0.23 ± 0.14, respectively (p < 0.001). CONCLUSIONS: Both horizontal and vertical transportation causes a significant increase in ICP and iPRx in patients with severe TBI, potentially leading to the outcome worsening.

Cerebral Microcirculation and Oxygenation Modulation by Transcranial Alternating Current Stimulation in Awake and Anesthetized Mice.

Transcranial alternating current stimulation (tACS) is a novel non-invasive electrical stimulation technique where a sinusoidal oscillating low-voltage electric current is applied to the brain. TACS is being actively investigated in practice for cognition and behavior modulation and for treating brain disorders. However, the physiological mechanisms of tACS are underinvestigated and poorly understood. Previously, we have shown that transcranial direct current stimulation (tDCS) facilitates cerebral microcirculation and oxygen supply in a mouse brain through nitric oxide-dependent vasodilatation of arterioles. Considering that the effects of tACS and tDCS might be both similar and dissimilar, we tested the effects of tACS on regional cerebral blood flow and oxygen saturation in anesthetized and awake mice using laser speckle contrast imaging and multispectral intrinsic optical signal imaging. The anesthetized mice were imaged under isoflurane anesthesia ∼1.0% in 30% O2 and 70% N2O. The awake mice were pre-trained on the rotating ball for awake imaging. Baseline imaging with further tACS was followed by post-stimulation imaging for ~3 h. Differences between groups were determined using a two-way ANOVA analysis for multiple comparisons and post hoc testing using the Mann-Whitney U test. TACS increased cerebral blood flow and oxygen saturation. In awake mice, rCBF and oxygen saturation responses were more robust and prolonged as opposed to anesthetized, where the response was weaker and shorter with overshoot. The significant difference between anesthetized and awake mice emphasizes the importance of the experiments on the latter as anesthesia is not typical for human stimulation and significantly alters the results.

Mechanisms of Photostimulation of Brain's Waste Disposal System: The Role of Singlet Oxygen.

There is strong evidence that augmentation of the brain's waste disposal system via stimulation of the meningeal lymphatics might be a promising therapeutic target for preventing neurological diseases. In our previous studies, we demonstrated activation of the brain's waste disposal system using transcranial photostimulation (PS) with a laser 1267 nm, which stimulates the direct generation of singlet oxygen in the brain tissues. Here we investigate the mechanisms underlying this phenomenon. Our results clearly demonstrate that PS-mediated stimulation of the brain's waste disposal system is accompanied by activation of lymphatic contractility associated with subsequent intracellular production of the reactive oxygen species and the nitric oxide underlying lymphatic relaxation. Thus, PS stimulates the brain's waste disposal system by influencing the mechanisms of regulation of lymphatic pumping.

Changes of Arterial and Venous Cerebral Blood Flow Correlation in Moderate-to-Severe Traumatic Brain Injury: A CT Perfusion Study.

We compared differences in perfusion computed tomography (PCT)-derived arterial and venous cerebral blood flow (CBF) in moderate-to-severe traumatic brain injury (TBI) as an indication of changes in cerebral venous outflow patterns referenced to arterial inflow. Moderate-to-severe TBI patients (women 53; men 74) underwent PCT and were stratified into 3 groups: I (moderate TBI), II (diffuse severe TBI without surgery), and III (diffuse severe TBI after the surgery). Arterial and venous CBF was measured by PCT in both the middle cerebral arteries (CBFmca) and the upper sagittal sinus (CBFuss). In group I, CBFmca on the left and right sides were significantly correlated with each other (p < 0.0001) and with CBFuss (p = 0.048). In group II, CBFmca on the left and right sides were also correlated (p < 0.0000001) but not with CBFuss. Intracranial pressure reactivity (PRx) and CBFuss were correlated (p = 0.00014). In group III, CBFmca on the side of the removed hematoma was not significantly different from the opposite CBFmca (p = 0.680) and was not correlated with CBFuss. Conclusions: The increasing severity of TBI is accompanied by an impairment of the correlation between the arterial and venous CBF in the supratentorial vessels suggesting shifting in arterial and venous CBF in severe TBI associated with increased ICP reflected by PRx.

Cerebral Net Water Uptake in Posttraumatic Cerebral Ischemia.

We assessed net water uptake changes (NWU) in regions of posttraumatic ischemia in relation to cerebral microcirculation mean transit time (MTT) at moderate-to-severe traumatic brain injury (TBI). MATERIALS AND METHODS: 128 moderate-to-severe traumatic brain injury patients (44 women, 84 men, age: 37 ± 12 years) were stratified into 3 groups: Marshall 2-3: 48 patients, Marshall 4: 44 patients, Marshall 5: 36 patients. The groups were matched by sex and age. Patients received multiphase perfusion computed tomography (PCT) 1-5 days after admission. Net water uptake was calculated from non-contrast computed tomography. Data are shown as a median [interquartile range]. P < 0.05 was considered statistically significant. RESULTS: Cerebral blood flow in posttraumatic ischemia foci in Marshall 4 group was significantly higher than that in the Marshall 5 group (p = 0.027). Net water uptake in posttraumatic ischemia zones was significantly higher than in zones without posttraumatic ischemia (8.1% versus 4.2%, p < 0.001). Mean transit time in posttraumatic ischemia zones was inversely and significantly correlated with higher net water uptake (R2 = 0,089, p < 0.01). CONCLUSIONS: Delay of blood flow through the cerebral microvascular bed was significantly correlated with the increased net water uptake in posttraumatic ischemia foci. Marshall's classification did not predict the progression of posttraumatic ischemia.

Sex-Specific and Dose-Dependent Effects of Drag-Reducing Polymers on Microcirculation and Tissue Oxygenation in Rats After Traumatic Brain Injury.

Traumatic brain injury (TBI) ultimately leads to a reduction in the cerebral metabolic rate for oxygen due to ischemia. Previously, we showed that 2 ppm i.v. of drag-reducing polymers (DRP) improve hemodynamic and oxygen delivery to tissue in a rat model of mild-to-moderate TBI. Here we evaluated sex-specific and dose-dependent effects of DRP on microvascular CBF (mvCBF) and tissue oxygenation in rats after moderate TBI. In vivo two-photon laser scanning microscopy over the rat parietal cortex was used to monitor the effects of DRP on microvascular perfusion, tissue oxygenation, and blood-brain barrier (BBB) permeability. Lateral fluid-percussion TBI (1.5 ATA, 100 ms) was induced after baseline imaging and followed by 4 h of monitoring. DRP was injected at 1, 2, or 4 ppm within 30 min after TBI. Differences between groups were determined using a two-way ANOVA analysis for multiple comparisons and post hoc testing using the Mann-Whitney U test. Moderate TBI progressively decreased mvCBF, leading to tissue hypoxia and BBB degradation in the pericontusion zone (p < 0.05). The i.v. injection of DRP increased near-wall flow velocity and flow rate in arterioles, leading to an increase in the number of erythrocytes entering capillaries, enhancing capillary perfusion and tissue oxygenation while protecting BBB in a dose-dependent manner without significant difference between males and females (p < 0.01). TBI resulted in an increase in intracranial pressure (20.1 ± 3.2 mmHg, p < 0.05), microcirculatory redistribution to non-nutritive microvascular shunt flow, and stagnation of capillary flow, all of which were dose-dependently mitigated by DRP. DRP at 4 ppm was most effective, with a non-significant trend to better outcomes in female rats.

Photostimulation of brain lymphatics in male newborn and adult rodents for therapy of intraventricular hemorrhage.

Intraventricular hemorrhage is one of the most fatal forms of brain injury that is a common complication of premature infants. However, the therapy of this type of hemorrhage is limited, and new strategies are needed to reduce hematoma expansion. Here we show that the meningeal lymphatics is a pathway to remove red blood cells from the brain's ventricular system of male human, adult and newborn rodents and is a target for non-invasive transcranial near infrared photobiomodulation. Our results uncover the clinical significance of phototherapy of intraventricular hemorrhage in 4-day old male rat pups that have the brain similar to a preterm human brain. The course of phototherapy in newborn rats provides fast recovery after intraventricular hemorrhage due to photo-improvements of lymphatic drainage and clearing functions. These findings shed light on the mechanisms of phototherapy of intraventricular hemorrhage that can be a clinically relevant technology for treatment of neonatal intracerebral bleedings.

Transcranial Photosensitizer-Free Laser Treatment of Glioblastoma in Rat Brain.

Over sixty years, laser technologies have undergone a technological revolution and become one of the main tools in biomedicine, particularly in neuroscience, neurodegenerative diseases and brain tumors. Glioblastoma is the most lethal form of brain cancer, with very limited treatment options and a poor prognosis. In this study on rats, we demonstrate that glioblastoma (GBM) growth can be suppressed by photosensitizer-free laser treatment (PS-free-LT) using a quantum-dot-based 1267 nm laser diode. This wavelength, highly absorbed by oxygen, is capable of turning triplet oxygen to singlet form. Applying 1267 nm laser irradiation for a 4 week course with a total dose of 12.7 kJ/cm2 firmly suppresses GBM growth and increases survival rate from 34% to 64%, presumably via LT-activated apoptosis, inhibition of the proliferation of tumor cells, a reduction in intracranial pressure and stimulation of the lymphatic drainage and clearing functions. PS-free-LT is a promising breakthrough technology in non- or minimally invasive therapy for superficial GBMs in infants as well as in adult patients with high photosensitivity or an allergic reaction to PSs.

Moderate Severity SARS-CoV-2 (COVID-19) Affects Ocular Vergence Indices: Eye Tracking-Based Study.

OBJECTIVE: Since the start of the SARS-CoV-2 (COVID-19) pandemic, it has become clear that the brain is one of the main targets for acute and chronic damage. Although neurodegenerative changes have yet to be investigated, there is already a large body of data on damage to its fiber tracts. A mobile eye tracker is possibly one of the best tools to study such damage in a COVID hospital setting. At the same time, the available data indicate that eye tracking parameters, even in healthy volunteers, demonstrate a distinct gender-specific difference.The aim of the work is to evaluate functional and structural impairments of the fiber tracts and to find possible gender-specific dynamics of eye tracking indicators in the acute period of COVID-19 pneumonia (Delta variant) of moderate severity. MATERIALS AND METHODS: A single-center non-randomized retrospective study included 84 patients in the acute period of moderate severity SARS-CoV-2 (COVID-19) pneumonia (Delta variant) (Group 1). The mean time from admission was 1.4 ± 1.2 days. M:41, F:43. According to thoracic CT, the lung involvement ranged from CT 1 to CT 2. SpO2 ranged from 95% to 99%. The mean age was 35.5 ± 14.8 years (from 18 to 60). The control group (Group 2) included 158 healthy volunteers without pathology of the vision organs and central nervous system.The eye vergence index (VRx) was determined using eye tracking as a motion correlation coefficient between the angular velocities of the left and right eyeballs and was a measure of the conjugation of horizontal and vertical eye movements.The mobile complex Eye Tracker Low-Speed 20 (BVG LLC, the Netherlands) was used. Eye tracking parameters were assessed by vertical and horizontal eye vergence (VVRx and HVRx).Statistical analysis was done using the methods of parametric and non-parametric statistics. RESULTS: Moderate COVID-19 pneumonia resulted in a significant decrease in both VVRx and HVRx compared to controls (0.763 ± 0.127 and 0.856 ± 0.043; p < 0.000001; 0.729 ± 0.018 and 0.776 ± 0.023 p < 0.000001, respectively). VVRx values were significantly higher in men (0.775 ± 0.046 and 0.747 ± 0.091, p = 0.019, respectively), while Ð¥VRx values were significantly higher in women (0.665 ± 0.018 and 0.728 ± 0.024, p < 0.0000001, respectively). CONCLUSIONS: SARS-CoV-2 (COVID-19) of moderate severity is accompanied by a significant deterioration in eye tracking performance proving functional and structural impairments (p < 0.05). VVRx was significantly higher in men, and HVRx was substantially greater in women reflecting gender-specific differences.

Non-Invasive Vagus Nerve Stimulation Improves Brain Lesion Volume and Neurobehavioral Outcomes in a Rat Model of Traumatic Brain Injury.

Abstract Traumatic brain injury (TBI) continues to be a major cause of death and disability worldwide. This study assessed the effectiveness of non-invasive vagus nerve stimulation (nVNS) in reducing brain lesion volume and improving neurobehavioral performance in a rat model of TBI. Animals were randomized into three experimental groups: (1) TBI with sham stimulation treatment (Control), (2) TBI treated with five lower doses (2-min) nVNS, and (3) TBI treated with five higher doses (2 × 2-min) nVNS. We used the gammaCore nVNS device to deliver stimulations. Magnetic resonance imaging studies were performed 1 and 7 days post-injury to confirm lesion volume. We observed smaller brain lesion volume in the lower dose nVNS group compared with the control group on days 1 and 7. The lesion volume for the higher dose nVNS group was significantly smaller than either the lower dose nVNS or the control groups on days 1 and 7 post-injury. The apparent diffusion coefficient differences between the ipsilateral and contralateral hemispheres on day 1 were significantly smaller for the higher dose (2 × 2 min) nVNS group than for the control group. Voxel-based morphometry analysis revealed an increase in the ipsilateral cortical volume in the control group caused by tissue deformation and swelling. On day 1, these abnormal volume changes were 13% and 55% smaller in the lower dose and higher dose nVNS groups, respectively, compared with the control group. By day 7, nVNS dampened cortical volume loss by 35% and 89% in the lower dose and higher dose nVNS groups, respectively, compared with the control group. Rotarod, beam walking, and anxiety performances were significantly improved in the higher-dose nVNS group on day 1 compared with the control group. The anxiety indices were also improved on day 7 post-injury compared with the control and the lower-dose nVNS groups. In conclusion, the higher dose nVNS (five 2 × 2-min stimulations) reduced brain lesion volume to a level that further refined the role of nVNS therapy for the acute treatment of TBI. Should nVNS prove effective in additional pre-clinical TBI models and later in clinical settings, it would have an enormous impact on the clinical practice of TBI in both civilian and military settings, as it can easily be adopted into routine clinical practice.

Comparison of Cerebral Autoregulation Above and Below the Tentorium of the Cerebellum In Neurosurgical Patients with Transtentorial ICP Gradient.

INTRODUCTION: Cerebral autoregulation is an essential mechanism for maintaining cerebral blood flow stability. The phenomenon of transtentorial intracranial pressure (ICP) gradient after neurosurgical operations, complicated by edema and intracranial hypertension in the posterior fossa, has been described in clinical practice but is still underinvestigated. The aim of the study was to compare autoregulation coefficients (i.e., pressure reactivity index [PRx]) in two compartments (infratentorial and supratentorial) during the ICP gradient phenomenon. METHODS: Three male patients, aged 24 years, 32 years, and 59 years, respectively, were involved in the study after posterior fossa surgery. Arterial blood pressure and ICP were invasively monitored. Infratentorial ICP was measured in the cerebellar parenchyma. Supratentorial ICP was measured either in the parenchyma of the cerebral hemispheres or through the external ventricular drainage. Cerebral autoregulation was evaluated by the PRx coefficient (ICM + , Cambridge, UK). RESULTS: In all patients, ICP was higher in the posterior fossa, and the transtentorial ICP gradient in each patient was 5 ± 1.6 mm Hg, 8.5 ± 4.4 mm Hg, and 7.7 ± 2.2 mm Hg, respectively. ICP in the infratentorial space was 17 ± 4 mm Hg, 18 ± 4.4 mm Hg, and 20 ± 4 mm Hg, respectively. PRx values in the supratentorial and infratentorial spaces had the smallest difference (- 0.01, 0.02, and 0.01, respectively), and the limits of precision were 0.1, 0.2, and 0.1 in the first, second, and third patients, respectively. The correlation coefficient between the PRx values in the supratentorial and infratentorial spaces for each patient was 0.98, 0.95, and 0.97, respectively. CONCLUSIONS: A high degree of correlation was established between the autoregulation coefficient PRx in two compartments in the presence of transtentorial ICP gradient and persistent intracranial hypertension in the posterior fossa. Cerebral autoregulation, according to the PRx coefficient in both spaces, was similar.

Low-Level Laser Treatment Induces the Blood-Brain Barrier Opening and the Brain Drainage System Activation: Delivery of Liposomes into Mouse Glioblastoma.

The progress in brain diseases treatment is limited by the blood-brain barrier (BBB), which prevents delivery of the vast majority of drugs from the blood into the brain. In this study, we discover unknown phenomenon of opening of the BBBB (BBBO) by low-level laser treatment (LLLT, 1268 nm) in the mouse cortex. LLLT-BBBO is accompanied by activation of the brain drainage system contributing effective delivery of liposomes into glioblastoma (GBM). The LLLT induces the generation of singlet oxygen without photosensitizers (PSs) in the blood endothelial cells and astrocytes, which can be a trigger mechanism of BBBO. LLLT-BBBO causes activation of the ABC-transport system with a temporal decrease in the expression of tight junction proteins. The BBB recovery is accompanied by activation of neuronal metabolic activity and stabilization of the BBB permeability. LLLT-BBBO can be used as a new opportunity of interstitial PS-free photodynamic therapy (PDT) for modulation of brain tumor immunity and improvement of immuno-therapy for GBM in infants in whom PDT with PSs, radio- and chemotherapy are strongly limited, as well as in adults with a high allergic reaction to PSs.

Photobiomodulation and nitric oxide signaling.

Nitric oxide (NO) is a well-known gaseous mediator that maintains vascular homeostasis. Extensive evidence supports that a hallmark of endothelial dysfunction, which leads to cardiovascular diseases, is endothelial NO deficiency. Thus, restoring endothelial NO represents a promising approach to treating cardiovascular complications. Despite many therapeutic agents having been shown to augment NO bioavailability under various pathological conditions, success in resulting clinical trials has remained elusive. There is solid evidence of diverse beneficial effects of the treatment with low-power near-infrared (NIR) light, defined as photobiomodulation (PBM). Although the precise mechanisms of action of PBM are still elusive, recent studies consistently report that PBM improves endothelial dysfunction via increasing bioavailable NO in a dose-dependent manner and open a feasible path to the use of PBM for treating cardiovascular diseases via augmenting NO bioavailability. In particular, the use of NIR light in the NIR-II window (1000-1700 nm) for PBM, which has reduced scattering and minimal tissue absorption with the largest penetration depth, is emerging as a promising therapy. In this review, we update recent findings on PBM and NO.

Involvement of Endothelial Nitric Oxide Synthase in Cerebral Microcirculation and Oxygenation in Traumatic Brain Injury.

Traumatic brain injury (TBI) leads to cerebral microvascular dysfunction and cerebral ischemia. Endothelial nitric oxide synthase (eNOS) is a key regulator of vascular homeostasis. We aimed to assess the role of eNOS in cerebral blood flow (CBF) changes after TBI. Moderate TBI was induced in eNOS knockout (KO) and wild-type (WT) mice (8 per group). Cerebral microvascular tone, microvascular CBF (mCBF) and tissue oxygenation (NADH) were measured by two-photon laser scanning microscopy (2PLSM) before and 1 h, 1 day and 3 days after TBI. Cerebrovascular reactivity (CVR) was evaluated by the hypercapnia test. Laser Doppler cortical flux (cLDF) was simultaneously measured in the perilesional area. One hr after TBI, cLDF was 59.4 ± 8.2% and 60.3 ± 9.1% from the baseline (p < 0.05) in WT and eNOS KO, respectively. 2PLSM showed decreased arteriolar diameter, the number of functioning capillaries, mCBF and tissue oxygenation (p < 0.05). At 1 day, cLDF increased to 65.2 ± 6.4% in the WT group, while it decreased to 56.1 ± 7.2% in the eNOS KO mice. 2PLSM revealed a further decrease in the number of functioning capillaries, mCBF, and oxygen supply which was slightly milder in WT mice (p < 0.05 from the baseline). On the third day after TBI, cLDF increased to 72 ± 5.2% in the WT, while it stayed the same in the eNOS KO group (55.9 ± 6.4%, p < 0.05 from the WT). 2PLSM showed reduction in arterioles with vasospasm, increase in the number of functioning capillaries, and improvement in mCBF and tissue oxygen supply in WT, while no significant changes were observed in eNOS KO (p < 0.05). CVR was impaired in both groups 1 h after TBI, and improved by the third day in the WT, while staying impaired in eNOS KO. In the subacute TBI period, the significance of eNOS in maintaining cerebral microcirculation and oxygen supply increases with time after the injury.

NIRS-Based Study of Local Cerebral Oxygenation During Transcranial Direct Current Stimulation in Patients with Mild Traumatic Brain Injury.

The purpose of our study was to assess the dynamics of local cerebral oxygenation (LCO) by near-infrared spectroscopy (NIRS) during transcranial direct current stimulation (tDCS) in the acute stage of mild traumatic brain injury (mTBI). Fifty-seven mTBI patients (18 women and 39 men, 35 ± 11.7 years old, GCS 13.7 ± 0.7) were treated by tDCS at 3-5 days after head injury. Stimulation parameters were: 1 mA, 9 V, duration-20 min. A cerebral oximeter was used to assess LCO-values in the frontotemporal lobes. Anodal and cathodal LCO values were compared before tDCS and every 2 min until the tDCS end. Significance was preset to p < 0.05. Results: A significant decrease in LCO values on the anodal side was observed at the 8th to 12th minutes of stimulation, compared to the cathodal side (at 8th minute - p = 0.011; at 12th minute - p < 0.00000001) and compared to LCO values before tDCS (p < 0.00001). The LCO on the cathodal side was not significantly different during the whole tDCS. At the end of the procedure, the interhemispheric LCO differences were not statistically significant (p = 0.757). Conclusions: Transcranial DCS in 3-5 days of mTBI leads to a significant decrease in the LCO value on the anodal side between 8 and 12 min and subsequent recovery to baseline values by the end of the procedure.

Low Flow and Microvascular Shunts: A Final Common Pathway to Cerebrovascular Disease: A Working Hypothesis.

Low flow and microvascular shunts (MVS) is the final common pathway in cerebrovascular disease. Low flow in brain capillaries (diam. 3-8 µm) decreases endothelial wall shear rate sensed by the glycocalyx regulating endothelial function: water permeability; nitric oxide synthesis via nitric oxide synthase; leucocyte adhesion to the endothelial wall and penetration into the tissue; activation of cytokines and chemokines initiating inflammation in tissue. Tissue edema combined with pericyte and astrocyte capillary constriction increases capillary resistance. Increased capillary resistance diverts flow through MVS (diam. 10-25 µm) that are non-nutritive, without gas exchange, waste or metabolite clearance and cerebral blood flow (CBF) regulation. MVS predominate in subcortical and periventricular white matter. The shift in flow from capillaries to MVS is a pathological, maladaptive process. Low perfusion in the injured tissue exacerbates brain edema. Low blood flow and MVS alone can lead to all of the processes involved in tissue injury including inflammation and microglial activation.

Eye Tracking Parameters Correlate with the Level of Cerebral Oxygen Saturation in Mild Traumatic Brain Injury: A Preliminary Study.

AIM: The aim of this study was to assess the relationship between oculomotor synergies and brain oxygen status at mild traumatic brain injury (mTBI) using simultaneous comparison of eye-tracking (ET) parameters and cerebral oxygen saturation. MATERIAL AND METHODS: This non-randomised single-centre prospective study included 77 patients with mTBI (mean age was 36.3 ± 4.8 years, 48 men, 29 women, median GCS 13.7 ± 0.7). Cerebral oximetry was used to detect oxygen saturation level (SctO2) in the frontal lobe pole (FLP) region. Eye movements were measured simultaneously using the EyeTracker. Calculated parameters were: vertical and horizontal angular eyeball velocity (AV); left vertical speed (LVS); right vertical speed (RVS); left horizontal speed (LHS); and right horizontal speed (RHS). The indices of vertical and horizontal eye version (version index, Vx) were calculated as the Pearson correlation coefficient between the corresponding AV of the right and left eyes. Significance was pre-set to p < 0.05. RESULTS: SctO2 in the FLP varied from 62% to 79%. The average SctO2 values were 69.26 ± 6.96% over the left FLP and 70.25 ± 7.58% over the right FLP (p = 0.40). The total analysis of the eye-tracking data revealed the following values of gaze parameters: LVS - 0.327 ± 0.263 rad/sec; LHS - 0.201 ± 0.164 rad/sec; RVS - 0.361 ± 0.269 rad/sec; and RHS - 0.197 ± 0.124 rad/sec. The calculated vertical version index (VVx) was 0.80 ± 0.12. The calculated horizontal version index (HVx) was 0.82 ± 0.11. The VVx and HVx were correlated with SctO2 levels in the FLP (p = 0.038; r = 0.235; p = 0.048; r = 0.218, respectively p = 0.035; r = 0.241; p = 0.039; r = 0.235, respectively). CONCLUSIONS: VVx and HVx correlate with the SctO2 level in the FLP (p < 0.01) in mTBI. No significant correlation was detected between the level of the SctO2 level and vertical and horizontal AV of the eyeballs. Eye tracking can help quantify the severity of ocular conjugation impairments after mTBI, as well as explore the contribution that cerebral oxygen status disorders make to this process.