Brain Injury, Microcirculation and Tissue Perfusion

Neurocritical care focuses on monitoring cerebral blood flow (CBF) to prevent secondary brain injuries before damage becomes irreversible. Thus, there is a critical unmet need for continuous neuromonitoring methods to quantify CBF within the vulnerable cortex continuously and non-invasively. Animal models and imaging biomarkers can provide valuable insights into the mechanisms and kinetics of head injury, as well as insights for potential treatment strategies. For this purpose, we implemented an optical technique for continuous monitoring of blood flow changes after a closed head injury in a mouse model, which is based on laser speckle contrast imaging and a fiber camera-based approach. Our results indicate a significant decrease (~10%, p-value < 0.05) in blood flow within 30 min of a closed head injury. Furthermore, the low-frequency oscillation analysis also indicated much lower power in the trauma group compared to the control group. Overall, blood flow has the potential to be a biomarker for head injuries in the early phase of a trauma, and the system is useful for continuous monitoring with the potential for clinical translation. Full article

Identifying predictors for individuals vulnerable to the adverse effects of traumatic brain injury (TBI) remains an ongoing research pursuit. This is especially important for patients with mild TBI (mTBI), whose condition is often overlooked. TBI severity in humans is determined by several criteria, including the duration of loss of consciousness (LOC): LOC < 30 min for mTBI and LOC > 30 min for moderate-to-severe TBI. However, in experimental TBI models, there is no standard guideline for assessing the severity of TBI. One commonly used metric is the loss of righting reflex (LRR), a rodent analogue of LOC. However, LRR is highly variable across studies and rodents, making strict numeric cutoffs difficult to define. Instead, LRR may best be used as predictor of symptom development and severity. This review summarizes the current knowledge on the associations between LOC and outcomes after mTBI in humans and between LRR and outcomes after experimental TBI in rodents. In clinical literature, LOC following mTBI is associated with various adverse outcome measures, such as cognitive and memory deficits; psychiatric disorders; physical symptoms; and brain abnormalities associated with the aforementioned impairments. In preclinical studies, longer LRR following TBI is associated with greater motor and sensorimotor impairments; cognitive and memory impairments; peripheral and neuropathology; and physiologic abnormalities. Because of the similarities in associations, LRR in experimental TBI models may serve as a useful proxy for LOC to contribute to the ongoing development of evidence-based personalized treatment strategies for patients sustaining head trauma. Analysis of highly symptomatic rodents may shed light on the biological underpinnings of symptom development after rodent TBI, which may translate to therapeutic targets for mTBI in humans. Full article

Introduction: Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterized by neurological symptoms and distinctive neuroimaging findings. There are a few cases reported in the literature in which PRES can occur after surgery, and there is no clear direct relationship between a procedure and its debut. Methods: We performed a review of the literature by analyzing all reported cases of PRES syndrome which debuted after a surgical procedure with the aim of identifying the clinical features, the timing of the symptoms’ onset and the therapy of patients suffering from this unusual surgical complication. Results: The total number of patients collected was 47, with a mean age of 40.9 years. Postoperative PRES can occur in either pediatric or adult patients (ages 4–82 years). The most frequent form of comorbidity reported was cardiovascular disease (fourteen patients, 29.78%). Sixteen patients (36%) had no relevant risk factors or comorbidities at the time of the surgical procedure. The types of surgery most correlated were cranial neuro and maxillofacial surgery (twenty-one patients, 44.68%) followed by transplant surgery (eight patients, 17%). The time of onset of PRES after surgery occurred within the first 3 weeks (mean time of onset 4.7 days), and when rapidly treated with antihypertensive and antiepileptic drugs appeared to have a reversible and benign course. Conclusion: PRES syndrome can be considered a rare complication of procedures and can occur following a wide range of surgeries, especially cranial and transplant surgery. Being able to recognize it in time and treat it ensures a full reversibility of symptoms in most cases. Full article

Guillain-Barré syndrome (GBS) is a severe peripheral neuroinflammatory demyelinating disease characterized by symmetrical progressive limb weakness, which can be accompanied by cranial nerve and sensory disturbances. There is usually a history of bacterial or viral infection prior to onset. GBS is rarely seen after traumatic brain injury (TBI). We report a case of a 66-year-old male patient who presented with dilated pupils, followed by respiratory failure and symmetrical quadriplegia during a conservative treatment for TBI. He was eventually diagnosed with GBS and was treated with intravenous immunoglobulin, followed by rehabilitation therapy with a good recovery. We summarize previous similar cases and analyze possible causes. It is suggested that the possibility of GBS should be considered when unexplained symptoms occurred in patients with TBI, such as respiratory failure, dilated pupils, and limb weakness. Full article

Few data about the electroencephalogram and its calculated indices, such as the bispectral index (BIS), have been reported in rabbits. We aimed to evaluate whether a clinically stable anesthesia was mirrored by consistent and stable BIS values and to investigate the effects of modified cerebral blood supply, due to bilateral carotid clamping and re-opening, on BIS values. We also investigated the effects of fentanyl, as an antinociceptive drug, on the BIS. Sixty-eight rabbits undergoing general anesthesia for surgical creation of carotid bifurcation aneurysms were enrolled. The BIS values were recorded at nine selected time points (TPs) during each procedure and before and after fentanyl administration. The BIS values over time were compared with two-way repeated-measures analysis of variance followed by Tukey test, while the Wilcoxon signed rank test was performed to compare values at clamping and re-opening of the carotids as well as before and after fentanyl administration. The BIS values were significantly lower during anesthesia than at the end of anesthesia and at tracheal extubation; no significant differences were found among other TPs. Adequate depth of anesthesia was mirrored by consistent BIS values among rabbits, and alteration of cerebral blood supply did not modify BIS values, except once. Following fentanyl, BIS values did not change in a clinically relevant way. Full article

Explosive blasts are associated with neurological consequences as a result of blast waves impact on the brain. Yet, the neuropathologic and molecular consequences due to blast waves vs. blunt-TBI are not fully understood. An explosive-driven blast-generating system was used to reproduce blast wave exposure and examine pathological and molecular changes generated by primary wave effects of blast exposure. We assessed if pre- and post-synaptic (synaptophysin, PSD-95, spinophilin, GAP-43), neuronal (NF-L), glymphatic (LYVE1, podoplanin), myelin (MBP), neurovascular (AQP4, S100β, PDGF) and genomic (DNA polymerase-β, RNA polymerase II) markers could be altered across different brain regions of double blast vs. sham animals. Twelve male rats exposed to two consecutive blasts were compared to 12 control/sham rats. Western blot, ELISA, and immunofluorescence analyses were performed across the frontal cortex, hippocampus, cerebellum, and brainstem. The results showed altered levels of AQP4, S100β, DNA-polymerase-β, PDGF, synaptophysin and PSD-95 in double blast vs. sham animals in most of the examined regions. These data indicate that blast-generated changes are preferentially associated with neurovascular, glymphatic, and DNA repair markers, especially in the brainstem. Moreover, these changes were not accompanied by behavioral changes and corroborate the hypothesis for which an asymptomatic altered status is caused by repeated blast exposures. Full article

The animal thromboembolic model of ischemia perfectly mimics human ischemic stroke which remains the leading cause of disability and mortality in humans. The development of new treatment strategies was therefore imperative. The purpose of this study is to improve the thromboembolic stroke model in rats in order to design experiments that use motor tests, and are in accordance with the 3R principles to prevent complications and maintain the same size of the infarct repeatedly. Tail vein dye application, a protective skull mask and a stress minimization protocol were used as additional modifications to the animal stroke model. These modifications significantly minimized the pain and stress severity of the procedures in this model. In our experimental group of Long-Evans rats, a photo-induced stroke was caused by the application of a photosensitive dye (Rose Bengal) activated with white-light irradiation, thus eliminating the need to perform a craniotomy. The animals’ neurological status was evaluated using a runway elevated test. Histological examination of the brain tissue was performed at 12, 24 and 48 h, and seven days post-stroke. Tissue examination revealed necrotic foci in the cortex and the subcortical regions of the ipsilateral hemisphere in all experimental groups. Changes in the area, width and depth of the necrotic focus were observed over time. All the experimental groups showed motor disturbances after stroke survival. In the proposed model, photochemically-induced stroke caused long-term motor deficits, showed high reproducibility and low mortality rates. Consequently, the animals could participate in motor tests which are particularly suitable for assessing the efficacy of neuro-regenerative therapies, while remaining in line with the latest trends in animal experimental design. Full article

Background: The diagnosis of hydrocephalus is mainly based on imaging findings. However, the significance of many imaging indicators may change, especially in some degenerative diseases, and even lead to misdiagnosis. Methods: This study explored the effectiveness of commonly used morphological parameters and typical radiographic findings in hydrocephalus diagnosis. The patients’ imaging data were divided into three groups, including the hydrocephalus group, the symptomatic group, and the normal control group. The diagnostic validity and weight of various parameters were compared between groups by multiple machine learning methods. Results: Our results demonstrated that Evans’ ratio is the most valuable diagnostic indicator compared to the hydrocephalus group and the normal control group. But frontal horns’ ratio is more useful in diagnosing patients with symptoms. Meanwhile, the sign of disproportionately enlarged subarachnoid space and third ventricle enlargement could be effective diagnostic indicators in all situations. Conclusion: Both morphometric parameters and radiological features were essential in diagnosing hydrocephalus, but the weights are different in different situations. The machine learning approaches can be applied to optimize the diagnosis of other diseases and consistently update the clinical diagnostic criteria. Full article

(1) Background: Cerebral autoregulation is altered during acute mild traumatic brain injury, or concussion. However, it is unknown how a history of concussion can impact cerebral haemodynamic activity during a task that elicits an autoregulatory response. (2) Methods: We assessed cerebral haemodynamic activity in those with a history of three or more concussions. The study included 44 retired athletes with concussion history and 25 control participants. We recorded participants’ relative changes in right and left pre-frontal cortex oxygenation collected by near-infrared spectroscopy and continuous beat-to-beat blood pressure measured by finger photoplethysmography. Participants completed a 5-min seated rest followed by a 5-min repeated squat (10-s) stand (10-s) maneuver (0.05 Hz) to elicit a cerebral autoregulatory response. Wavelet transformation was applied to the collected signals, allowing separation into cardiac interval I (0.6 to 2 Hz), respiratory interval II (0.145 to 0.6 Hz), and smooth muscle cell interval III (0.052 to 0.145 Hz). (3) Results: Significant increases at cardiac interval I were found for the wavelet amplitude of oxy-haemoglobin and haemoglobin difference at the right pre-frontal cortex. No significant difference was found at the left pre-frontal cortex or the blood pressure wavelet amplitudes. (4) Conclusions: Contributions from cardiac activity to the pre-frontal cortex oxygenation are elevated when eliciting dynamic cerebral autoregulation in those with a history of three or more concussions. Full article

(1) Background: In recent years, “new” direct oral anticoagulants (DOAC) have gradually replaced other antithrombotic therapies. The international literature agrees on the increased mortality for traumatic brain injury (TBI) patients using vitamin K antagonists (VKA), but thus far, there are insufficient data on the influence of DOAC on the outcome of TBI. (2) Methods: We retrospectively analyzed data from all patients who presented with head trauma using antithrombotic therapy. Outcome parameters were the presence of pathologies on the initial CT, occurrence of delayed intracranial hemorrhage, surgical intervention, and death. (3) Results: In total, data of 1169 patients were reviewed. Of those, 1084 (92.7%) had a mild TBI, 67 (5.7%) moderate TBI, and 17 (1.5%) severe TBI. In total, 456 patients (39%) used DOAC and 713 patients (61%) used VKA, antiplatelet therapy, or prophylactic doses of low molecular weight heparin at the time of trauma. The groups showed no significant differences in age, injury mechanisms, or GCS at presentation. Overall, the initial cranial CT showed pathologies in 85 patients (7.3%). Twenty-five patients with head trauma and DOAC therapy had pathological findings on CT (5.5%), 11 patients with VKA (4.8%), and 48 patients with antiplatelet therapy (10.6%). There was a statistically significant difference in occurrence of CT pathologies between DOAC alone compared to acetylsalicylic acid (4.9 vs. 10.5%, p = 0.04). Delayed intracranial hemorrhage after an initially negative CT during in-hospital observation occurred in one patient (0.2%) in the DOAC group, two patients (0.9%) in the VKA group, and four patients (0.9%) in the antiplatelet group without statistical significance. Head trauma related surgery was performed in three patients (0.7%) in the DOAC group, two patients (0.9%) in the VKA group, and six patients (1.3%) in the antiplatelet group without statistical significance. Death due to head trauma occurred in four patients (0.9%) of the DOAC group compared to one patient (0.4%) of the VKA group and five patients (1.1%) of the antiplatelet group without statistical significance. (4) Conclusions: Our data suggest a comparable risk of pathological CT findings, delayed intracranial hemorrhage, surgical interventions, and death after blunt head trauma for patients with DOAC compared to VKA, but a lower risk for pathological CT findings compared to platelet inhibitors. As VKA are known to increase mortality, our data suggest that similar caution should be used when treating patients with head trauma and DOAC, but the overall numbers of serious or severe courses after simple falls remain low. We recommend routine CT for all head trauma patients with antithrombotic therapy but the role of in-hospital observation for patients with mild TBI remains a matter of debate. Full article

Post-traumatic headache (PTH) is the most common sequelae of traumatic brain injury (TBI). Its phenotypic variability, absence of formal evidence-based guidelines for treatment and underdiagnosis have made its management a challenge for clinicians. As a result, treatment of PTH has been mostly empiric. Although analgesics are the most popular drug of choice for PTH, they can present with several adverse effects and fail to address other psychosocial comorbidities associated with TBI. Non-pharmacological interventions thereby offer an intriguing alternative that can provide patients with PTH sustainable and effective care. This review article aims to: (1) provide an update on and describe different non-pharmacological interventions present in the recent literature; (2) provide clinical guidance to providers struggling with the management of patients with PTH; (3) emphasize the need for more high-quality trials examining the effectiveness of non-pharmacological treatments in patients with PTH. This review discusses 21 unique non-pharmacological treatments used for the management of PTH. Current knowledge of non-pharmacological interventions for the treatment of PTH is based on smaller scale studies, highlighting the need for larger randomized controlled trials to help establish formal evidence-based guidelines. Full article

Exosomes are nano-sized vesicles that contain a variety of mRNAs, miRNAs, and proteins. They are capable of being released by a variety of cells and are essential for cell–cell communication. The exosomes produced by cells have shown protective benefits against spinal cord damage (SCI). Recently, it was discovered that M2 macrophages aid in the angiogenesis of numerous illnesses. However, the functional role of M2 macrophage-derived exosomes on SCI is unclear. Here, we investigate the pro-angiogenesis of M2 macrophage-derived exosomes on SCI. We founded that M2 macrophage exosomes alleviated tissue damage and enhanced functional recovery post-SCI. We discovered that M2 macrophage exosome administration increased angiogenesis after SCI in vivo using immunohistochemistry, immunofluorescence labeling, and Western blot analysis. Additionally, the expression of the pro-angiogenesis factors, HIF-1α and VEGF, were enhanced with the treatment of the M2 macrophage exosomes. Furthermore, we found that M2 macrophage exosomes enhanced neurogenesis after SCI in vivo. In vitro, we found that M2 macrophage exosomes can be taken up by the brain endothelial cell line (bEnd.3) and that they enhanced the tube formation, migration, and proliferation of bEnd.3 cells. Furthermore, by using special siRNA to inhibit HIF-1α expression, we observed that the expression of VEGF decreased, and the tube formation, migration, and proliferation of bEnd.3 cells were attenuated with the treatment of HIF-1α-siRNA. In conclusion, our findings reveal that M2 macrophage exosomes improve neurological functional recovery and angiogenesis post-SCI, and this process is partially associated with the activation of the HIF-1/VEGF signaling pathway. Full article

Introduction: The aim of the study was to analyze risk factors for hematoma expansion (HE) in patients undergoing decompressive hemicraniectomy (DC) in patients with elevated intracranial pressure due to spontaneous intracerebral hematoma (ICH). Methods: We retrospectively evaluated 72 patients with spontaneous ICH who underwent DC at our institution. We compared the pre- and postoperative volumes of ICH and divided the patients into two groups: first, patients with postoperative HE > 6 cm³ (group 1), and second, patients without HE (group 2). Additionally, we screened the medical history for anticoagulant and antiplatelet medication (AC/AP), bleeding-related comorbidities, age, admission Glasgow coma scale and laboratory parameters. Results: The rate of AC/AP medication was higher in group 1 versus group 2 (15/16 vs. 5/38, p < 0.00001), and patients were significantly older in group 1 versus group 2 (65.1 ± 16.2 years vs. 54.4 ± 14.3 years, p = 0.02). Furthermore, preoperative laboratory tests showed lower rates of hematocrit (34.1 ± 5.4% vs. 38.1 ± 5.1%, p = 0.01) and hemoglobin (11.5 ± 1.6 g/dL vs. 13.13 ± 1.8 g/dL, p = 0.0028) in group 1 versus group 2. In multivariate analysis, the history of AC/AP medication was the only independent predictor of HE (p < 0.0001, OR 0.015, CI 95% 0.001–0.153). Conclusion: We presented a comprehensive evaluation of risk factors for hematoma epansion by patients undergoing DC due to ICH. Full article

Gasdermin D-executing pyroptosis mediated by NLRP3 inflammasomes has been recognized as a key pathogenesis during stroke. Hydrogen sulfide (H₂S) could protect CNS against ischemia/reperfusion (I/R)-induced neuroinflammation, while the underlying mechanism remains unclear. The study applied the middle cerebral artery occlusion/reperfusion (MCAO/R) model to investigate how the brain and the retinal injuries were alleviated in sodium hydrogen sulfide (NaHS)-treated rats. The rats were assigned to four groups and received an intraperitoneal injection of 50 μmol/kg NaHS or NaCl 15 min after surgery. Neurological deficits were evaluated using the modified neurologic severity score. The quantification of pro-inflammatory cytokines, NLRP3, caspase-1, and GSDMD were determined by ELISA and Western blot. Cortical and retinal neurodegeneration and cell pyroptosis were determined by histopathologic examination. Results showed that NaHS rescued post-stroke neurological deficits and infarct progression, improved retina injury, and attenuated neuroinflammation in the brain cortexes and the retinae. NaHS administration inhibits inflammation by blocking the NLRP3/caspase-1/GSDMD pathway and further suppressing neuronal pyroptosis. This is supported by the fact that it reversed the high-level of NLRP3, caspase-1, and GSDMD following I/R. Our findings suggest that compounds with the ability to donate H₂S could constitute a novel therapeutic strategy for ischemic stroke. Full article

During a stroke, a series of biochemical and metabolic changes occur which eventually lead to the death of cells by necrosis or apoptosis. This is a multi-stage process involving oxidative stress and an inflammatory response from the first signs of occlusion of a blood vessel until the late stages of regeneration and healing of ischemic tissues. The purpose of the research was to assess the concentration of pro-inflammatory cytokines IL-6 and TNF-α in the blood serum of patients with ischemic stroke (AIS) and to investigate their role as new markers in predicting functional prognosis after thrombolytic therapy. The researches have shown that the concentrations of the measured biomarkers were higher compared to the control group. Serum levels of IL-6 and THF-α before the initiation of intravenous thrombolysis were lower in the subgroup of patients with a favourable functional result (mRS: 0–2 pts) compared to the group of patients with an unfavourable functional result (mRS: 3–6 pts). A positive correlation was found between the concentration of IL-6 and TNF-α in patients with AIS during <4.5 h and on one day after the onset of stroke, which means that the concentration of IL-6 increases with the increase in TNF-α concentration. It has also been shown that higher levels of IL-6 in the acute phase of stroke and on the first and seventh days, and TNF-α during onset, were associated with poorer early and late prognosis in patients treated with intravenous thrombolysis. A relationship was found between the level of IL-6 and TNF-α in the subacute AIS and the severity of the neurological deficit. It has been shown that the investigated biomarkers may be a prognostic factor in the treatment of thrombolytic AIS. Full article