On Net Water Uptake in Posttraumatic Ischemia Foci.

BACKGROUND: The influence of cerebral edema and resultant secondary complications on the clinical outcome of traumatic brain injury (TBI) is well known. Clinical studies of brain water homeostasis dynamics in TBI are limited, which determines the relevance of our work. The purpose is to study changes in brain water homeostasis after TBI of varying severity compared to corresponding cerebral microcirculation parameters. MATERIALS: This non-randomized retrospective single-center study complies with the Helsinki Declaration for patient's studies. The study included 128 patients with posttraumatic ischemia (PCI) after moderate-to-severe TBI in the middle cerebral artery territory who were admitted to the hospital between July 2015 and February 2022. PCI was evaluated by perfusion computed tomography (CT), and brain edema was determined using net water uptake (NWU) on baseline CT images. The patients were allocated according to Marshall's classification. Multivariate linear regression models were performed to analyze data. RESULTS: NWU in PCI areas were significantly higher than in patients with its absence (8.1% vs. 4.2%, accordingly; p < 0.001). In the multivariable regression analysis, the mean transit time increase was significantly and independently associated with higher NWU (R2 = 0.089, p < 0.01). In the PCI zone, cerebral blood flow, cerebral blood volume, and time to peak were not significantly associated with NWU values (p > 0.05). No significant differences were observed between the NWU values in PCI foci in different Marshall groups (p = 0.308). CONCLUSION: Marshall's classification does not predict the progression of posttraumatic ischemia. The blood passage delays through the cerebral microvascular bed is associated with brain tissue water content increase in the PCI focus.

Assessment of Optimal Arterial Pressure with Near-Infrared Spectroscopy in Traumatic Brain Injury Patients.

In patients with severe traumatic brain injury (TBI), simultaneous measurement of intracranial and arterial blood pressure (ICP and ABP, respectively) allows monitoring of cerebral perfusion pressure (CPP) and the assessment of cerebral autoregulation (CA). CPP, a difference between ICP and ABP, is the pressure gradient that drives oxygen delivery to cerebral tissue. CA is the ability of cerebral vasculature to maintain stable blood flow despite changes in CPP and thus, is an important homeostatic mechanism. Pressure reactivity index (PRx), a moving Pearson's correlation between slow waves in ICP and ABP, has been most frequently cited in literature over the past two decades as a tool for CA evaluation. However, in some clinical situations, ICP monitoring may be unavailable or contraindicated. In such cases, simultaneous mean arterial pressure (MAP) monitoring and near-infrared spectroscopy (NIRS) can be used for CA assessment by cerebral oximetry index (COx), allowing calculation of the optimal blood pressure (MAPOPT). The purpose of this study was to compare regional oxygen saturation (rSO2)-based CA (COx) with ICP/ABP-based CA (PRx) in TBI patients and to compare MAPOPT derived from both technologies. Three TBI patients were monitored at the bedside to measure CA using both PRx and COx. Patients were monitored daily for up to 3 days from TBI. Averaged PRx and COx-, and PRx and COx-based MAPOPT were compared using Pearson's correlation. Bias analysis was performed between these same CA metrics. Correlation between averaged values of COx and PRx was R = 0.35, p = 0.15. Correlation between optimal MAP calculated for COx and PRx was R = 0.49, p < 0.038. Bland-Altman analysis showed moderate agreement with a bias of 0.16 ± 0.23 for COx versus PRx and good agreement with a bias of 0.39 ± 7.89 for optimal MAP determined by COx versus PRx. Non-invasive measurement of CA by NIRS (COx) is not correlated with invasive ICP/ABP-based CA (PRx). However, the determination of MAPOPT using COx is correlated with MAPOPT derived from PRx. Obtained results demonstrate that COx is not an acceptable substitute for PRx in TBI patients. However, in some TBI cases, NIRS may be useful in determining MAP determination.

Haemorheologic Enhancement of Cerebral Perfusion Improves Oxygen Supply and Reduces Aß Plaques Deposition in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a consequence of complex interactions of age-related neurodegeneration and vascular-associated pathologies, affecting more than 44 million people worldwide. For the last decade, it has been suggested that chronic brain hypoperfusion and consequent hypoxia play a direct role in the pathogenesis of AD. However, current treatments of AD have not focused on restoring or improving microvascular perfusion. In a previous study, we showed that drag reducing polymers (DRP) enhance cerebral blood flow and tissue oxygenation. We hypothesised that haemorheologic enhancement of cerebral perfusion by DRP would be useful for treating Alzheimer's disease. We used double transgenic B6C3-Tg(APPswe, PSEN1dE9) 85Dbo/Mmjax AD mice. DRP or vehicle (saline) was i.v. injected every week starting at four months of age till 12 months of age (10 mice/group). In-vivo 2-photon laser scanning microscopy was used to evaluate amyloid plaques development, cerebral microcirculation, and tissue oxygen supply/metabolic status (NADH autofluorescence). The imaging sessions were repeated once a month till 12 months of age. Statistical analyses were done by independent Student's t-test or Kolmogorov-Smirnov tests where appropriate. Differences between groups and time were determined using a two-way repeated measures ANOVA analysis for multiple comparisons and post hoc testing using the Mann-Whitney U test. In the vehicle group, numerous plaques completely formed in the cortex by nine months of age. The development of plaques accumulation was accompanied by cerebral microcirculation disturbances, reduction in tissue oxygen supply and metabolic impairment (NADH increase). DRP mitigated microcirculation and tissue oxygen supply reduction - microvascular perfusion was 29.5 ± 5%, and tissue oxygen supply was 22 ± 4% higher than in the vehicle group (p < 0.05). In the DRP group, amyloid plaques deposition was substantially less than in the vehicle group (p < 0.05). Thus, rheological enhancement of blood flow by DRP is associated with reduced rate of beta amyloid plaques deposition in AD mice.

Transcranial Photobiomodulation of Clearance of Beta-Amyloid from the Mouse Brain: Effects on the Meningeal Lymphatic Drainage and Blood Oxygen Saturation of the Brain.

Here, we demonstrate the therapeutic effects of transcranial photobiomodulation (tPBM, 1267 nm, 32 J/cm2, a 9-day course) in mice with the injected model of Alzheimer's disease (AD) associated with accumulation of beta-amyloid (Aß) in the brain resulting in neurocognitive deficit vs. the control group (CG) (the neurological severity score (NNS), AD 3.67 ± 0.58 vs. CG 1.00 ± 0.26%, p < 0.05) and mild cerebral hypoxia (AD 72 ± 6% vs. CG 97 ± 2%, p < 0.001). The course of tPBM improved neurocognitive status of mice with AD (NNS, AD 2.03 ± 0.14 vs. CG 1.00 ± 0.26, vs. 2.03 ± 0.14, p < 0.05) due to stimulation of clearance of Aß from the brain via the meningeal lymphatic vessels (the immunohistochemical and confocal data) and an increase in blood oxygen saturation of the brain tissues (the pulse oximetry data) till 85 ± 2%, p < 0.05. These results open breakthrough strategies for non-pharmacological therapy of AD and clearly demonstrate that tPBM might be a promising therapeutic target for preventing or delaying AD based on stimulation of oxygenation of the brain tissues and activation of clearance of toxic molecules via the cerebral lymphatics.

Mechanisms of Sound-Induced Opening of the Blood-Brain Barrier.

The blood-brain barrier (BBB) poses a significant challenge for drug delivery to the brain. The limitations of our knowledge about the nature of BBB explain the slow progress in the therapy of brain diseases and absence of methods for drug delivery to the brain in clinical practice. Here, we show that the BBB opens for high-molecular-weight compounds after exposure to loud sound (100 dB 370 Hz) in rats. The role of stress induced by loud sound and the systemic and molecular mechanisms behind it are discussed in the framework of the BBB. This opens an informative platform for novel fundamental knowledge about the nature of BBB and for the development of a noninvasive brain drug delivery technology.

Phenomenon of music-induced opening of the blood-brain barrier in healthy mice.

Music plays a more important role in our life than just being an entertainment. For example, it can be used as an anti-anxiety therapy of human and animals. However, the unsafe listening of loud music triggers hearing loss in millions of young people and professional musicians (rock, jazz and symphony orchestra) owing to exposure to damaging sound levels using personal audio devices or at noisy entertainment venues including nightclubs, discotheques, bars and concerts. Therefore, it is important to understand how loud music affects us. In this pioneering study on healthy mice, we discover that loud rock music below the safety threshold causes opening of the blood-brain barrier (OBBB), which plays a vital role in protecting the brain from viruses, bacteria and toxins. We clearly demonstrate that listening to loud music during 2 h in an intermittent adaptive regime is accompanied by delayed (1 h after music exposure) and short-lasting to (during 1-4 h) OBBB to low and high molecular weight compounds without cochlear and brain impairments. We present the systemic and molecular mechanisms responsible for music-induced OBBB. Finally, a revision of our traditional knowledge about the BBB nature and the novel strategies in optimizing of sound-mediated methods for brain drug delivery are discussed.

Increases in Microvascular Perfusion and Tissue Oxygenation via Vasodilatation After Anodal Transcranial Direct Current Stimulation in the Healthy and Traumatized Mouse Brain.

Traumatic brain injury (TBI), causing neurological deficit in 70% of survivors, still lacks a clinically proven effective therapy. Transcranial direct current stimulation (tDCS) has emerged as a promising electroceutical therapeutic intervention possibly suitable for TBI; however, due to limited animal studies the mechanisms and optimal parameters are unknown. Using a mouse model of TBI we evaluated the acute effects of the anodal tDCS on cerebral blood flow (CBF) and tissue oxygenation, and assessed its efficacy in long-term neurologic recovery. TBI was induced by controlled cortical impact leading to cortical and hippocampal lesions with reduced CBF and developed hypoxia in peri-contusion area. Sham animals were subjected to craniotomy only. Repetitive anodal tDCS (0.1 mA/15 min) or sham stimulation was done over 4 weeks for four consecutive days with 3-day intervals, beginning 1 or 3 weeks after TBI. Laser speckle contrast imaging (LSCI) revealed that anodal tDCS causes an increase in regional cortical CBF in both traumatized and Sham animals. On microvascular level, using in-vivo two-photon microscopy (2PLSM), we have shown that anodal tDCS induces arteriolar dilatation leading to an increase in capillary flow velocity and tissue oxygenation in both traumatized and Sham animals. Repetitive anodal tDCS significantly improved motor and cognitive neurologic outcome. The group with stimulation starting 3 weeks after TBI showed better recovery compared with stimulation starting 1 week after TBI, suggesting that the late post-traumatic period is more optimal for anodal tDCS.

Resuscitation Fluid with Drag Reducing Polymer Enhances Cerebral Microcirculation and Tissue Oxygenation After Traumatic Brain Injury Complicated by Hemorrhagic Shock.

Traumatic brain injury (TBI) is frequently accompanied by hemorrhagic shock (HS) which significantly worsens morbidity and mortality. Existing resuscitation fluids (RF) for volume expansion inadequately mitigate impaired microvascular cerebral blood flow (mvCBF) and hypoxia after TBI/HS. We hypothesized that nanomolar quantities of drag reducing polymers in resuscitation fluid (DRP-RF), would improve mvCBF by rheological modulation of hemodynamics. METHODS: TBI was induced in rats by fluid percussion (1.5 atm, 50 ms) followed by controlled hemorrhage to a mean arterial pressure (MAP) = 40 mmHg. DRP-RF or lactated Ringer (LR-RF) was infused to MAP of 60 mmHg for 1 h (pre-hospital), followed by blood re-infusion to a MAP = 70 mmHg (hospital). Temperature, MAP, blood gases and electrolytes were monitored. In vivo 2-photon laser scanning microscopy was used to monitor microvascular blood flow, hypoxia (NADH) and necrosis (i.v. propidium iodide) for 5 h after TBI/HS followed by MRI for CBF and lesion volume. RESULTS: TBI/HS compromised brain microvascular flow leading to capillary microthrombosis, tissue hypoxia and neuronal necrosis. DRP-RF compared to LR-RF reduced microthrombosis, restored collapsed capillary flow and improved mvCBF (82 ± 9.7% vs. 62 ± 9.7%, respectively, p < 0.05, n = 10). DRP-RF vs LR-RF decreased tissue hypoxia (77 ± 8.2% vs. 60 ± 10.5%, p < 0.05), and neuronal necrosis (21 ± 7.2% vs. 36 ± 7.3%, respectively, p < 0.05). MRI showed reduced lesion volumes with DRP-RF. CONCLUSIONS: DRP-RF effectively restores mvCBF, reduces hypoxia and protects neurons compared to conventional volume expansion with LR-RF after TBI/HS.

Improvement of Impaired Cerebral Microcirculation Using Rheological Modulation by Drag-Reducing Polymers.

Nanomolar intravascular concentrations of drag-reducing polymers (DRP) have been shown to improve hemodynamics and survival in animal models of ischemic myocardium and limb, but the effects of DRP on the cerebral microcirculation have not yet been studied. We recently demonstrated that DRP enhance microvascular flow in normal rat brain and hypothesized that it would restore impaired microvascular perfusion and improve outcomes after focal ischemia and traumatic brain injury (TBI). We studied the effects of DRP (high molecular weight polyethylene oxide, 4000 kDa, i.v. at 2 µg/mL of blood) on microcirculation of the rat brain: (1) after permanent middle cerebral artery occlusion (pMCAO); and (2) after TBI induced by fluid percussion. Using in vivo two-photon laser scanning microscopy (2PLSM) over the parietal cortex of anesthetized rats we showed that both pMCAO and TBI resulted in progressive decrease in microvascular circulation, leading to tissue hypoxia (NADH increase) and increased blood brain barrier (BBB) degradation. DRP, injected post insult, increased blood volume flow in arterioles and red blood cell (RBC) flow velocity in capillaries mitigating capillary stasis, tissue hypoxia and BBB degradation, which improved neuronal survival (Fluoro-Jade B, 24 h) and neurologic outcome (Rotarod, 1 week). Improved microvascular perfusion by DRP may be effective in the treatment of ischemic stroke and TBI.