Traumatic brain injury and Alzheimer's disease share pathological similarities, including neuronal loss, amyloid-β deposition, tau hyperphosphorylation, blood-brain barrier dysfunction, neuroinflammation, and cognitive deficits. Furthermore, traumatic brain injury can exacerbate Alzheimer's disease-like pathologies, potentially leading to the development of Alzheimer's disease. Nanocarriers offer a potential solution by facilitating the delivery of small interfering RNAs across the blood-brain barrier for the targeted silencing of key pathological genes implicated in traumatic brain injury and Alzheimer's disease. Unlike traditional approaches to neuroregeneration, this is a molecular-targeted strategy, thus avoiding non-specific drug actions. This review focuses on the use of nanocarrier systems for the efficient and precise delivery of siRNAs, discussing the advantages, challenges, and future directions. In principle, siRNAs have the potential to target all genes and non-targetable proteins, holding significant promise for treating various diseases. Among the various therapeutic approaches currently available for neurological diseases, siRNA gene silencing can precisely "turn off" the expression of any gene at the genetic level, thus radically inhibiting disease progression; however, a significant challenge lies in delivering siRNAs across the blood-brain barrier. Nanoparticles have received increasing attention as an innovative drug delivery tool for the treatment of brain diseases. They are considered a potential therapeutic strategy with the advantages of being able to cross the blood-brain barrier, targeted drug delivery, enhanced drug stability, and multifunctional therapy. The use of nanoparticles to deliver specific modified siRNAs to the injured brain is gradually being recognized as a feasible and effective approach. Although this strategy is still in the preclinical exploration stage, it is expected to achieve clinical translation in the future, creating a new field of molecular targeted therapy and precision medicine for the treatment of Alzheimer's disease associated with traumatic brain injury.

Markers of cerebral metabolism measured by microdialysis (CMD) may warn clinicians of impending neuroworsening in patients with severe acute brain injury. This retrospective study investigated the relationship between systemic glucose levels and microdialysate glucose (CMD-glucose) in patients with severe traumatic brain injury (TBI) or aneurysmal subarachnoid haemorrhage (SAH).

We retrospectively investigated patients who underwent CMD. Linear regression and correlation analysis between temporally matched values of systemic and CMD-glucose were performed. Disease severity was dichotomized using the Glasgow Coma Scale score (GCS) at admission, and patient outcome at 6 months was dichotomized using the modified Rankin Scale.

Data was available from 133 patients, of which 75 had SAH and 58 had TBI. The R2 suggested that systemic glucose levels explained 31% (95% CI: 14-39) of CMD-glucose variation in SAH patients and 15% (95% CI: 5-45) in TBI patients. In a linear regression model, CMD-glucose increased by 0.16 (95% CI: 0.16-0.17) for patients with SAH and 0.17 (95% CI: 0.16-0.18) mmol/L for patients with TBI for every 1 mmol/L increase in systemic glucose. Furthermore, both systemic and CMD-glucose decreased with increasing time from ictus. We found no association between CMD-glucose and disease severity or functional outcome.

In this retrospective analysis of patients with severe acute brain injury undergoing intracerebral microdialysis, changes in systemic glucose contributed to changes in CMD-glucose with no relation to functional outcome.

This study assessed microdialysis-derived brain tissue extracellular glucose levels, analysed together with serum glucose levels measured at the same time; this was in patients with acute brain injury with sampling in the less injured cerebral hemisphere. Findings demonstrated that there were predictable changes in microdialysate glucose levels when serum glucose levels changed. Neither of these glucose levels was associated with functional outcomes.

Clinicaltrials.gov identifier: NCT06302244.

Lactates accumulation following traumatic brain injury (TBI) is detrimental. However, whether lactylation is triggered and involved in the deterioration of TBI remains unknown. Here, we first report that Tufm lactylation pathway induces neuronal apoptosis in TBI. Lactylation is found significantly increased in brain tissues from patients with TBI and mice with controlled cortical impact (CCI), and in neuronal injury cell models. Tufm, a key factor in mitophagy, is screened and identified to be mostly lactylated. Tufm is detected to be lactylated at K286 and the lactylation inhibits the interaction of Tufm and Tomm40 on mitochondria. The mitochondrial distribution of Tufm is then inhibited. Consequently, Tufm-mediated mitophagy is suppressed while mitochondria-induced neuronal apoptosis is increased. In contrast, the knockin of a lactylation-deficient TufmK286R mutant in mice rescues the mitochondrial distribution of Tufm and Tufm-mediated mitophagy, and improves functional outcome after CCI. Likewise, mild hypothermia, as a critical therapeutic method in neuroprotection, helps in downregulating Tufm lactylation, increasing Tufm-mediated mitophagy, mitigating neuronal apoptosis, and eventually ameliorating the outcome of TBI. A novel molecular mechanism in neuronal apoptosis, TBI-initiated Tufm lactylation suppressing mitophagy, is thus revealed.

Brain energy metabolism is often disturbed after acute brain injuries. Current neuromonitoring methods with cerebral microdialysis (CMD) are based on intermittent measurements (1-4 times/h), but such a low frequency could miss transient but important events. The solution may be the recently developed Loke microdialysis (MD), which provides high-frequency data of glucose and lactate. Before clinical implementation, the reliability and stability of Loke remain to be determined in vivo. The purpose of this study was to validate Loke MD in relation to the standard intermittent CMD method.

Four pigs aged 2-3 months were included. They received two adjacent CMD catheters, one for standard intermittent assessments and one for continuous (Loke MD) assessments of glucose and lactate. The standard CMD was measured every 15 min. Continuous Loke MD was sampled every 2-3 s and was averaged over corresponding 15-min intervals for the statistical comparisons with standard CMD. Intravenous glucose injections and intracranial hypertension by inflation of an intracranial epidural balloon were performed to induce variations in intracranial pressure, cerebral perfusion pressure, and systemic and cerebral glucose and lactate levels.

In a linear mixed-effect model of standard CMD glucose (mM), there was a fixed effect value (± standard error [SE]) at 0.94 ± 0.07 (p < 0.001) for Loke MD glucose (mM), with an intercept at - 0.19 ± 0.15 (p = 0.20). The model showed a conditional R2 at 0.81 and a marginal R2 at 0.72. In a linear mixed-effect model of standard CMD lactate (mM), there was a fixed effect value (± SE) at 0.41 ± 0.16 (p = 0.01) for Loke MD lactate (mM), with an intercept at 0.33 ± 0.21 (p = 0.25). The model showed a conditional R2 at 0.47 and marginal R2 at 0.17.

The established standard CMD glucose thresholds may be used as for Loke MD with some caution, but this should be avoided for lactate.

The pathogenesis of ferroptosis in traumatic brain injury (TBI) is unclear; therefore, we aimed to identify key molecules associated with ferroptosis in TBI using bioinformatics analysis to determine its underlying mechanisms. GSE128543 dataset was downloaded from the Gene Expression Omnibus (GEO) database, and TBI-associated modules were obtained by weighted gene co-expression network analysis (WGCNA). We identified 60 differentially expressed genes (DEGs) by intersecting the modules with ferroptosis and glycolysis/gluconeogenesis gene libraries. The hypoxia-inducible factor-1 (HIF-1) signaling pathway was identified to be critical for ferroptosis post-TBI, and protein-protein interaction (PPI) network identified 20 hub genes, including phosphoglycerate kinase 1 (PGK1), ribosomal protein (RP) family, pyruvate kinase M1/2 (PKM), hypoxia-inducible factor 1α subunit (HIF-1α), and MYC genes. In this study, we further explored the role of PGK1, a gene involved in HIF-1 signaling pathway; however, its role and mechanism in TBI are still unclear. Moreover, we constructed a TBI mouse model and examined PGK1 and HIF-1α expression levels, and the results revealed their expressions increased after cortical injury in mice and they co-localized in the same cells. Furthermore, we examined the expressions of PGK1 in the cerebrospinal fluid of 20 clinical patients with different degrees of brain injuries within 48 h of surgery and examined the cognitive function of patients according to the Glasgow Coma Scale (GCS). The results revealed that PGK1 expression level was negatively correlated with the severity of the brain injury. These findings suggest that PGK1 may become a potential hub gene for ferroptosis via the HIF-1 signaling pathway, second to neurological injury after TBI, thereby affecting patient prognosis.

Brain takes up approximately 20% of the total body oxygen and glucose consumption due to its relatively high energy demand. Glucose is one of the major sources to generate ATP, the process of which can be realized via glycolysis, oxidative phosphorylation, pentose phosphate pathways and others. Lactate serves as a hub molecule amid these metabolic pathways, as it may function as product of glycolysis, substrate of a variety of enzymes and signal molecule. Thus, the roles of lactate in central nervous system (CNS) diseases need to be comprehensively elucidated. Histone lactylation is a novel lactate-dependent epigenetic modification that plays an important role in immune regulation and maintaining homeostasis. However, there's still a lack of studies unveiling the functions of histone lactylation in the CNS. In this review, we first comprehensively reviewed the roles lactate plays in the CNS under both physiological and pathological conditions. Subsequently, we've further discussed the functions of histone lactylation in various neurological diseases. Furthermore, future perspectives regarding histone lactylation and its therapeutic potentials in stroke are also elucidated, which may possess potential clinical applications.

Traumatic brain injury (TBI) poses a significant challenge to healthcare providers, necessitating meticulous management of hemodynamic parameters to optimize patient outcomes. This article delves into the critical task of defining and meeting continuous arterial blood pressure (ABP) and cerebral perfusion pressure (CPP) targets in the context of severe TBI in neurocritical care settings.

We narratively reviewed existing literature, clinical guidelines, and emerging technologies to propose a comprehensive approach that integrates real-time monitoring, individualized cerebral perfusion target setting, and dynamic interventions.

Our findings emphasize the need for personalized hemodynamic management, considering the heterogeneity of patients with TBI and the evolving nature of their condition. We describe the latest advancements in monitoring technologies, such as autoregulation-guided ABP/CPP treatment, which enable a more nuanced understanding of cerebral perfusion dynamics. By incorporating these tools into a proactive monitoring strategy, clinicians can tailor interventions to optimize ABP/CPP and mitigate secondary brain injury.

Challenges in this field include the lack of standardized protocols for interpreting multimodal neuromonitoring data, potential variability in clinical decision-making, understanding the role of cardiac output, and the need for specialized expertise and customized software to have individualized ABP/CPP targets regularly available. The patient outcome benefit of monitoring-guided ABP/CPP target definitions still needs to be proven in patients with TBI.

We recommend that the TBI community take proactive steps to translate the potential benefits of personalized ABP/CPP targets, which have been implemented in certain centers, into a standardized and clinically validated reality through randomized controlled trials.

Traumatic brain injury (TBI) remains a leading cause of death and disability that places a great physical, social, and financial burden on individuals and the health system. In this review, we summarize new research into the metabolic changes described in clinical TBI trials, some of which have already shown promise for informing injury classification and staging. We focus our discussion on derangements in glucose metabolism, cell respiration/mitochondrial function and changes to ketone and lipid metabolism/oxidation to emphasize potentially novel biomarkers for clinical outcome prediction and intervention and offer new insights into possible underlying mechanisms from preclinical research of TBI pathology. Finally, we discuss nutrition supplementation studies that aim to harness the gut/microbiome-brain connection and manipulate systemic/cellular metabolism to improve post-TBI recovery. Taken together, this narrative review summarizes published TBI-associated changes in glucose and lipid metabolism, highlighting potential metabolite biomarkers for clinical use, the cellular processes linking these markers to TBI pathology as well as the limitations and future considerations for TBI "omics" work.

Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits often associated with the development of neurodegenerative diseases. Oxidative stress and formation of reactive oxygen species (ROS) have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, we explore these pathogenic mechanisms utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice. We observed a significant elevation of Na+/H+ exchanger protein (NHE1) expression in GFAP+ reactive astrocytes, IBA1+ microglia, and OLIG2+ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus) after r-mTBI. This elevation was accompanied by astrogliosis, microgliosis, and the accumulation of amyloid precursor protein (APP). Mice subjected to r-mTBI displayed impaired motor learning and spatial memory. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function.

Cerebral microdialysis (CMD) catheters allow continuous monitoring of patients' cerebral metabolism in severe traumatic brain injury (TBI). The catheters consist of a terminal semi-permeable membrane that is inserted into the brain's interstitium to allow perfusion fluid to equalize with the surrounding cerebral extracellular environment before being recovered through a central non-porous channel. However, it is unclear how far recovered fluid and suspended metabolites have diffused from within the brain, and therefore what volume or region of brain tissue the analyses of metabolism represent. We assessed diffusion of the small magnetic resonance (MR)-detectible molecule gadobutrol from microdialysis catheters in six subjects (complete data five subjects, incomplete data one subject) who had sustained a severe TBI. Diffusion pattern and distance in cerebral white matter were assessed using T1 (time for MR spin-lattice relaxation) maps at 1 mm isotropic resolution in a 3 Tesla MR scanner. Gadobutrol at 10 mmol/L diffused from cerebral microdialysis catheters in a uniform spheroidal (ellipsoid of revolution) pattern around the catheters' semipermeable membranes, and across gray matter-white matter boundaries. Evidence of gadobutrol diffusion was found up to a mean of 13.4 ± 0.5 mm (mean ± standard deviation [SD]) from catheters, but with a steep concentration drop off so that ≤50% of maximum concentration was achieved at ∼4 mm, and ≤10% of maximum was found beyond ∼7 mm from the catheters. There was little variation between subjects. The relaxivity of gadobutrol in human cerebral white matter was estimated to be 1.61 ± 0.38 L.mmol-1sec-1 (mean ± SD); assuming gadobutrol remained extracellular thereby occupying 20% of total tissue volume (interstitium), and concentration equilibrium with perfusion fluid was achieved immediately adjacent to catheters after 24 h of perfusion. No statistically significant change was found in the concentration of the extracellular metabolites glucose, lactate, pyruvate, nor the lactate/pyruvate ratio during gadobutrol perfusion when compared with period of baseline microdialysis perfusion. Cerebral microdialysis allows continuous monitoring of regional cerebral metabolism-the volume of which is now clearer from this study. It also has the potential to deliver small molecule therapies to focal pathologies of the human brain. This study provides a platform for future development of new catheters optimally designed to treat such conditions.

The local effects of an intracerebral hemorrhage (ICH) on surrounding brain tissue can be detected bedside using multimodal brain monitoring techniques. The aim of this study is to design a gradient boosting regression model using the R package boostmtree with the ability to predict lactate-pyruvate ratio measurements in ICH.

We performed a retrospective analysis of 6 spontaneous ICH and 6 traumatic ICH patients who underwent surgical removal of the clot with microdialysis catheters placed in the perihematomal zone. Predictors of glucose, lactate, pyruvate, age, sex, diagnosis, and operation status were used to design our model.

In a holdout analysis, the model forecasted lactate-pyruvate ratio trends in a representative in-sample testing set. We anticipate that boostmtree could be applied to designs of similar regression models to analyze trends in other multimodal monitoring features across other types of acute brain injury.

The model successfully predicted hourly lactate-pyruvate ratios in spontaneous ICH and traumatic ICH cases after the hemorrhage evacuation and displayed significantly better performance than linear models. Our results suggest that boostmtree may be a powerful tool in developing more advanced mathematical models to assess other multimodal monitoring parameters for cases in which the perihematomal environment is monitored.

Traumatic brain injury (TBI) causes neuroinflammation and can lead to long-term neurological dysfunction, even in cases of mild TBI (mTBI). Despite the substantial burden of this disease, the management of TBI is precluded by an incomplete understanding of its cellular mechanisms. Sphingolipids (SPL) and their metabolites have emerged as key orchestrators of biological processes related to tissue injury, neuroinflammation, and inflammation resolution. No study so far has investigated comprehensive sphingolipid profile changes immediately following TBI in animal models or human cases. In this study, sphingolipid metabolite composition was examined during the acute phases in brain tissue and plasma of mice following mTBI.

Wildtype mice were exposed to air-blast-mediated mTBI, with blast exposure set at 50-psi on the left cranium and 0-psi designated as Sham. Sphingolipid profile was analyzed in brain tissue and plasma during the acute phases of 1, 3, and 7 days post-TBI via liquid-chromatography-mass spectrometry. Simultaneously, gene expression of sphingolipid metabolic markers within brain tissue was analyzed using quantitative reverse transcription-polymerase chain reaction. Significance (P-values) was determined by non-parametric t-test (Mann-Whitney test) and by Tukey's correction for multiple comparisons.

In post-TBI brain tissue, there was a significant elevation of 1) acid sphingomyelinase (aSMase) at 1- and 3-days, 2) neutral sphingomyelinase (nSMase) at 7-days, 3) ceramide-1-phosphate levels at 1 day, and 4) monohexosylceramide (MHC) and sphingosine at 7-days. Among individual species, the study found an increase in C18:0 and a decrease in C24:1 ceramides (Cer) at 1 day; an increase in C20:0 MHC at 3 days; decrease in MHC C18:0 and increase in MHC C24:1, sphingomyelins (SM) C18:0, and C24:0 at 7 days. Moreover, many sphingolipid metabolic genes were elevated at 1 day, followed by a reduction at 3 days and an absence at 7-days post-TBI. In post-TBI plasma, there was 1) a significant reduction in Cer and MHC C22:0, and an increase in MHC C16:0 at 1 day; 2) a very significant increase in long-chain Cer C24:1 accompanied by significant decreases in Cer C24:0 and C22:0 in MHC and SM at 3 days; and 3) a significant increase of C22:0 in all classes of SPL (Cer, MHC and SM) as well as a decrease in Cer C24:1, MHC C24:1 and MHC C24:0 at 7 days.

Alterations in sphingolipid metabolite composition, particularly sphingomyelinases and short-chain ceramides, may contribute to the induction and regulation of neuroinflammatory events in the early stages of TBI, suggesting potential targets for novel diagnostic, prognostic, and therapeutic strategies in the future.

To determine whether targeting mild hypercapnia (PaCO2 7 kPa) would yield improved cerebral blood flow and metabolism compared to normocapnia (PaCO2 5 kPa) with and without targeted temperature management to 33 °C (TTM33) in a porcine post-cardiac arrest model.

39 pigs were resuscitated after 10 minutes of cardiac arrest using cardiopulmonary bypass and randomised to TTM33 or no-TTM, and hypercapnia or normocapnia. TTM33 was managed with intravasal cooling. Animals were stabilized for 30 minutes followed by a two-hour intervention period. Hemodynamic parameters were measured continuously, and neuromonitoring included intracranial pressure (ICP), pressure reactivity index, cerebral blood flow, brain-tissue pCO2 and microdialysis. Measurements are reported as proportion of baseline, and areas under the curve during the 120 min intervention period were compared.

Hypercapnia increased cerebral flow in both TTM33 and no-TTM groups, but also increased ICP (199% vs. 183% of baseline, p = 0.018) and reduced cerebral perfusion pressure (70% vs. 84% of baseline, p < 0.001) in no-TTM animals. Cerebral lactate (196% vs. 297% of baseline, p < 0.001), pyruvate (118% vs. 152% of baseline, p < 0.001), glycerol and lactate/pyruvate ratios were lower with hypercapnia in the TTM33 group, but only pyruvate (133% vs. 150% of baseline, p = 0.002) was lower with hypercapnia among no-TTM animals.

In this porcine post-arrest model, hypercapnia led to increased cerebral flow both with and without hypothermia, but also increased ICP and reduced cerebral perfusion pressure in no-TTM animals. The effects of hypercapnia were different with and without TTM.(Institutional protocol number: FOTS, id 14931).

In managing severe traumatic brain injury (TBI), emergency surgery involving the removal of damaged brain tissue and intracerebral hemorrhage is a priority. Secondary brain injury caused by oxidative stress and energy metabolic disorders, triggered by both primary mechanical brain damage and surgical insult, is also a determining factor in the prognosis of TBI. Unfortunately, the effectiveness of traditional postoperative intravenous neuroprotective agents therapy is often limited by the lack of targeting, timeliness, and side effects when neuroprotective agents systemically delivered. Here, we have developed injectable, intelligent, self-assembling hydrogels (P-RT/2DG) that can achieve precise treatment through intraoperative application to the target area. P-RT/2DG hydrogels were prepared by integrating a reactive oxygen species (ROS)-responsive thioketal linker (RT) into polyethylene glycol. By scavenging ROS and releasing 2-deoxyglucose (2DG) during degradation, these hydrogels functioned both in antioxidation and energy metabolism to inhibit the vicious cycle of post-TBI ROS-lactate which provoked secondary injury. In vitro and in vivo tests confirmed the absence of systemic side effects and the neuroprotective function of P-RT/2DG hydrogels in reducing edema, nerve cell apoptosis, neuroinflammation, and maintaining the blood-brain barrier. Our study thus provides a potential treatment strategy with novel hydrogels in TBI.

Intrahospital transfer (IHT), a routine in the management of neurocritical patients requiring imaging or interventions, might affect brain metabolism. Studies about IHT effects using microdialysis (MD) have produced conflicting results. In these studies, only the most damaged hemisphere was monitored, and those may not reflect the impact of IHT on overall brain metabolism, nor do they address differences between the hemispheres. Herein we aimed to quantify the effect of IHT on brain metabolism by monitoring both hemispheres with bilateral MD. In this study, 27 patients with severe brain injury (10 traumatic brain injury and 17 subarachnoid hemorrhage patients) were included, with a total of 67 IHT. Glucose, glycerol, pyruvate and lactate were measured by MD in both hemispheres for 10 h pre- and post-IHT. Alterations in metabolite levels after IHT were observed on both hemispheres; although these changes were more marked in hemisphere A (most damaged) than B (less damaged). Our results suggest that brain metabolism is altered after an IHT of neurocritical ill patients particularly but not limited to the damaged hemisphere. Bilateral monitorization may be more sensitive than unilateral monitorization for detecting metabolic disturbances not directly related to the course of the disease.

Cerebral metabolic dysfunction is a critical pathological hallmark observed in the aftermath of traumatic brain injury (TBI), as extensively documented in clinical investigations and experimental models. An in-depth understanding of the bioenergetic disturbances that occur following TBI promises to reveal novel therapeutic targets, paving the way for the timely development of interventions to improve patient outcomes. The 13C isotope tracing technique represents a robust methodological advance, harnessing biochemical quantification to delineate the metabolic trajectories of isotopically labeled substrates. This nuanced approach enables real-time mapping of metabolic fluxes, providing a window into the cellular energetic state and elucidating the perturbations in key metabolic circuits. By applying this sophisticated tool, researchers can dissect the complexities of bioenergetic networks within the central nervous system, offering insights into the metabolic derangements specific to TBI pathology. Embraced by both animal studies and clinical research, 13C isotope tracing has bolstered our understanding of TBI-induced metabolic dysregulation. This review synthesizes current applications of isotope tracing and its transformative potential in evaluating and addressing the metabolic sequelae of TBI.

Metabolomic biomarkers hold promise in aiding the diagnosis and prognostication of traumatic brain injury. In Canada, over 165,000 individuals annually suffer from a traumatic brain injury (TBI), making it one of the most prevalent neurological conditions. In this pilot investigation, we examined blood-derived biomarkers as proxy measures that can provide an objective approach to TBI diagnosis and monitoring. Using a 1H nuclear magnetic resonance (NMR)-based quantitative metabolic profiling approach, this study determined whether (1) blood-derived metabolites change during recovery in male participants with mild to severe TBI; (2) biological pathway analysis reflects mechanisms that mediate neural damage/repair throughout TBI recovery; and (3) changes in metabolites correlate to initial injury severity. Eight male participants with mild to severe TBI (with intracranial lesions) provided morning blood samples within 1-4 days and again 6 months post-TBI. Following NMR analysis, the samples were subjected to multivariate statistical and machine learning-based analyses. Statistical modelling displayed metabolic changes during recovery through group separation, and eight significant metabolic pathways were affected by TBI. Metabolic changes were correlated to injury severity. L-alanine (R= -0.63, p < 0.01) displayed a negative relationship with the Glasgow Coma Scale. This study provides pilot data to support the feasibility of using blood-derived metabolites to better understand changes in biochemistry following TBI.

Traumatic brain injury remains a major cause of mortality and morbidity in children across the world. Current management based on international guidelines focuses on a fixed therapeutic target of less than 20 mm Hg for managing intracranial pressure and 40-50 mm Hg for cerebral perfusion pressure across the pediatric age group. To improve outcome from this complex disease, it is essential to understand the pathophysiological mechanisms responsible for disease evolution by using different monitoring tools. In this narrative review, we discuss the neuromonitoring tools available for use to help guide management of severe traumatic brain injury in children and some of the techniques that can in future help with individualizing treatment targets based on advanced cerebral physiology monitoring.

Cerebral microdialysis is a technique that enables monitoring of the neurochemistry of patients with significant acquired brain injury, such as traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH). Cerebral microdialysis can also be used to characterise the neuro-pharmacokinetics of small-molecule study substrates using retrodialysis/retromicrodialysis. However, challenges remain: (i) lack of a simple, stable, and inexpensive brain tissue model for the study of drug neuropharmacology; and (ii) it is unclear how far small study-molecules administered via retrodialysis diffuse within the human brain.

Here, we studied the radial diffusion distance of small-molecule gadolinium-DTPA from microdialysis catheters in a newly developed, simple, stable, inexpensive brain tissue model as a precursor for in-vivo studies. Brain tissue models consisting of 0.65% weight/volume agarose gel in two kinds of buffers were created. The distribution of a paramagnetic contrast agent gadolinium-DTPA (Gd-DTPA) perfusion from microdialysis catheters using magnetic resonance imaging (MRI) was characterized as a surrogate for other small-molecule study substrates.

We found the mean radial diffusion distance of Gd-DTPA to be 18.5 mm after 24 h (p < 0.0001).

Our brain tissue model provides avenues for further tests and research into infusion studies using cerebral microdialysis, and consequently effective focal drug delivery for patients with TBI and other brain disorders.

In traumatic brain injuries (TBI), cerebral microdialysis (CMD)-derived parameters, especially the lactate to pyruvate ratio (LP ratio), have been utilized for cerebral perfusion optimization. The objectives were to identify cerebral ischemia as measured by CMD in TBI patients requiring decompressive craniectomy and to observe the correlation between cerebral perfusion pressure (CPP), intracranial pressure (ICP), and CMD variables in these patients. Our secondary aim was to observe the effect of CPP augmentation on ischemia biomarkers.

After the Institute Ethics Committee approvals, seven adult patients requiring decompressive craniectomy following TBI were enrolled and CMD data were obtained prospectively for 72 h. CPP was augmented by 20% with noradrenaline infusion if LP ratio >40. Correlations were done with bootstrapping (n = 500) to obtain the confidence intervals (CI) due to the small sample size.

One patient had cerebral ischemia (median LP ratio of 265.5 and median pyruvate of 38 μmol/L), while another patient had non-ischemic mitochondrial dysfunction (median LP ratio 40.7 and median pyruvate 278.5). The coefficients of correlation between the LP ratio with CPP and ICP were r = -0.05 (CI = -0.14-0.03) and r = 0.09 (CI = -0.03-0.24), respectively. The coefficient of correlation between cerebral and blood glucose was r = 0.38, (CI - 0.35-0.14). Only two patients needed CPP augmentation, however, postaugmentation cerebral biochemistry did not change appreciably.

CMD can identify cerebral ischemia, however, no correlations were observed between the LP ratio and CPP or ICP. CPP augmentation did not improve cerebral biochemistry. More studies are required to understand and treat cerebral metabolism in TBI.

Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide, particularly among individuals under the age of 45. It is a complex, and heterogeneous disease with a multifaceted pathophysiology that remains to be elucidated. Metabolomics has the potential to identify metabolic pathways and unique biochemical profiles associated with TBI. Herein, we employed a longitudinal metabolomics approach to study TBI in a weight drop mouse model to reveal metabolic changes associated with TBI pathogenesis, severity, and secondary injury. Using proton nuclear magnetic resonance (1H NMR) spectroscopy, we biochemically profiled post-mortem brain from mice that suffered mild TBI (N = 25; 13 male and 12 female), severe TBI (N = 24; 11 male and 13 female) and sham controls (N = 16; 11 male and 5 female) at baseline, day 1 and day 7 following the injury. 1H NMR-based metabolomics, in combination with bioinformatic analyses, highlights a few significant metabolites associated with TBI severity and perturbed metabolism related to the injury. We report that the concentrations of taurine, creatinine, adenine, dimethylamine, histidine, N-Acetyl aspartate, and glucose 1-phosphate are all associated with TBI severity. Longitudinal metabolic observation of brain tissue revealed that mild TBI and severe TBI lead distinct metabolic profile changes. A multi-class model was able to classify the severity of injury as well as time after TBI with estimated 86% accuracy. Further, we identified a high degree of correlation between respective hemisphere metabolic profiles (r > 0.84, p < 0.05, Pearson correlation). This study highlights the metabolic changes associated with underlying TBI severity and secondary injury. While comprehensive, future studies should investigate whether: (a) the biochemical pathways highlighted here are recapitulated in the brain of TBI sufferers and (b) if the panel of biomarkers are also as effective in less invasively harvested biomatrices, for objective and rapid identification of TBI severity and prognosis.

Cerebral metabolic energy crisis (CMEC), often defined as a cerebrospinal fluid (CSF) lactate: pyruvate ratio (LPR) >40, occurs in various diseases and is associated with poor neurologic outcomes. Cerebral malaria (CM) causes significant mortality and neurodisability in children worldwide. Multiple factors that could lead to CMEC are plausible in these patients, but its frequency has not been explored. Fifty-three children with CM were enrolled and underwent analysis of CSF lactate and pyruvate levels. All 53 patients met criteria for a CMEC (median CSF LPR of 72.9 [interquartile range [IQR]: 58.5-93.3]). Half of children met criteria for an ischemic CMEC (median LPR of 85 [IQR: 73-184]) and half met criteria for a nonischemic CMEC (median LPR of 60 [IQR: 54-79]. Children also underwent transcranial doppler ultrasound investigation. Cerebral blood flow velocities were more likely to meet diagnostic criteria for low flow (<2 standard deviation from normal) or vasospasm in children with an ischemic CMEC (73%) than in children with a nonischemic CMEC (20%, p  = 0.04). Children with an ischemic CMEC had poorer outcomes (pediatric cerebral performance category of 3-6) than those with a nonischemic CMEC (46 vs. 22%, p  = 0.03). CMEC was ubiquitous in this patient population and the processes underlying the two subtypes (ischemic and nonischemic) may represent targets for future adjunctive therapies.

Complex metabolic disruption is a major aspect of the pathophysiology of traumatic brain injury (TBI). Pyruvate is an intermediate in glucose metabolism and considered one of the most clinically informative metabolites during neurocritical care of TBI patients, especially in deducing the lactate/pyruvate ratio (LPR) - a widely-used metric for probing the brain's metabolic redox state. LPR is conventionally measured offline on a bedside analyzer, on hourly accumulations of brain microdialysate. However, there is increasing interest within the field to quantify microdialysate pyruvate and LPR continuously in near-real-time within its pathophysiological range. We have previously measured pure standard pyruvate in-vitro using mid-infrared transmission, employing a commercially available external cavity-quantum cascade laser (EC-QCL) and a microfluidic flow cell and reported a limit of detection (LOD) of 0.1 mM.

The present study was to test whether the current commercially available state-of-the-art mid-infrared transmission system, can detect pyruvate levels lower than previously reported.

We measured pyruvate in perfusion fluid on the mid-infrared transmission system also equipped with an EC-QCL and microfluidic flow cells, tested at three pathlengths.

We characterised the system to extract its relevant figures-of-merit and report the LOD of 0.07 mM.

The reported LOD of 0.07 mM represents a clinically recognised threshold and is the lowest value reported in the field for a sensor that can be coupled to microdialysis. While work is ongoing for a definitive evaluation of the system to measuring pyruvate, these preliminary results set a good benchmark and reference against which future developments can be examined.

How to optimise glucose metabolism in the traumatised human brain remains unclear, including whether injured brain can metabolise additional glucose when supplied. We studied the effect of microdialysis-delivered 1,2-13C2 glucose at 4 and 8 mmol/L on brain extracellular chemistry using bedside ISCUSflex, and the fate of the 13C label in the 8 mmol/L group using high-resolution NMR of recovered microdialysates, in 20 patients. Compared with unsupplemented perfusion, 4 mmol/L glucose increased extracellular concentrations of pyruvate (17%, p = 0.04) and lactate (19%, p = 0.01), with a small increase in lactate/pyruvate ratio (5%, p = 0.007). Perfusion with 8 mmol/L glucose did not significantly influence extracellular chemistry measured with ISCUSflex, compared to unsupplemented perfusion. These extracellular chemistry changes appeared influenced by the underlying metabolic states of patients' traumatised brains, and the presence of relative neuroglycopaenia. Despite abundant 13C glucose supplementation, NMR revealed only 16.7% 13C enrichment of recovered extracellular lactate; the majority being glycolytic in origin. Furthermore, no 13C enrichment of TCA cycle-derived extracellular glutamine was detected. These findings indicate that a large proportion of extracellular lactate does not originate from local glucose metabolism, and taken together with our earlier studies, suggest that extracellular lactate is an important transitional step in the brain's production of glutamine.

Multifunctional devices that incorporate chemical or physical measurements combined with ways to manipulate brain tissue via drug delivery, electrical stimulation, or light for optogenetics are desired by neuroscientists. The next generation in vivo brain devices will likely utilize the extensive flexibility and rapid processing of 3D printing. This Perspective demonstrates how close we are to this reality for advanced neuroscience measurements. 3D printing provides the opportunity to improve microsampling-based devices in ways that have not been previously available. Not only can 3D printing be used for actual device creation, but it can also allow printing of peripheral objects necessary to assemble functional devices. The most probable 3D printing set up for microsampling devices with appropriate nm to μm feature size will likely require 2-photon polymerization-based printers. This Perspective describes the advantages and challenges for 3D printing of microsampling devices as an initial step to meet the next generation device needs of neuroscientists.

Emerging science continues to establish the detrimental effects of malnutrition in acute neurological diseases such as traumatic brain injury, stroke, status epilepticus and anoxic brain injury. The primary pathological pathways responsible for secondary brain injury include neuroinflammation, catabolism, immune suppression and metabolic failure, and these are exacerbated by malnutrition. Given this, there is growing interest in novel nutritional interventions to promote neurological recovery after acute brain injury. In this review, we will describe how malnutrition impacts the biomolecular mechanisms of secondary brain injury in acute neurological disorders, and how nutritional status can be optimized in both pediatric and adult populations. We will further highlight emerging therapeutic approaches, including specialized diets that aim to resolve neuroinflammation, immunodeficiency and metabolic crisis, by providing pre-clinical and clinical evidence that their use promotes neurologic recovery. Using nutrition as a targeted treatment is appealing for several reasons that will be discussed. Given the high mortality and both short- and long-term morbidity associated with acute brain injuries, novel translational and clinical approaches are needed.

Career athletes, active military, and head trauma victims are at increased risk for mild repetitive traumatic brain injury (rTBI), a condition that contributes to the development of epilepsy and neurodegenerative diseases. Standard clinical imaging fails to identify rTBI-induced lesions, and novel non-invasive methods are needed. Here, we evaluated if hyperpolarized 13C magnetic resonance spectroscopic imaging (HP 13C MRSI) could detect long-lasting changes in brain metabolism 3.5 months post-injury in a rTBI mouse model. Our results show that this metabolic imaging approach can detect changes in cortical metabolism at that timepoint, whereas multimodal MR imaging did not detect any structural or contrast alterations. Using Machine Learning, we further show that HP 13C MRSI parameters can help classify rTBI vs. Sham and predict long-term rTBI-induced behavioral outcomes. Altogether, our study demonstrates the potential of metabolic imaging to improve detection, classification and outcome prediction of previously undetected rTBI.

Altered levels of cerebrospinal fluid (CSF) glucose and lactate concentrations are associated with poor outcomes in acute brain injury patients. However, no data on changes in such metabolites consequently to therapeutic interventions are available. The aim of the study was to assess CSF glucose-to-lactate ratio (CGLR) changes related to therapies aimed at reducing intracranial pressure (ICP).

A multicentric prospective cohort study was conducted in 12 intensive care units (ICUs) from September 2017 to March 2022. Adult (> 18 years) patients admitted after an acute brain injury were included if an external ventricular drain (EVD) for intracranial pressure (ICP) monitoring was inserted within 24 h of admission. During the first 48-72 h from admission, CGLR was measured before and 2 h after any intervention aiming to reduce ICP ("intervention"). Patients with normal ICP were also sampled at the same time points and served as the "control" group.

A total of 219 patients were included. In the intervention group (n = 115, 53%), ICP significantly decreased and CPP increased. After 2 h from the intervention, CGLR rose in both the intervention and control groups, although the magnitude was higher in the intervention than in the control group (20.2% vs 1.6%; p = 0.001). In a linear regression model adjusted for several confounders, therapies to manage ICP were independently associated with changes in CGLR. There was a weak inverse correlation between changes in ICP and CGRL in the intervention group.

In this study, CGLR significantly changed over time, regardless of the study group. However, these effects were more significant in those patients receiving interventions to reduce ICP.

Invasive neuromonitoring has become an important part of pediatric neurocritical care, as neuromonitoring devices provide objective data that can guide patient management in real time. New modalities continue to emerge, allowing clinicians to integrate data that reflect different aspects of cerebral function to optimize patient management. Currently, available common invasive neuromonitoring devices that have been studied in the pediatric population include the intracranial pressure monitor, brain tissue oxygenation monitor, jugular venous oximetry, cerebral microdialysis, and thermal diffusion flowmetry. In this review, we describe these neuromonitoring technologies, including their mechanisms of function, indications for use, advantages and disadvantages, and efficacy, in pediatric neurocritical care settings with respect to patient outcomes.

Traumatic brain injury is a devastating event associated with substantial morbidity. Pathophysiology involves the initial trauma, subsequent inflammatory response, and secondary insults, which worsen brain injury severity. Management entails cardiopulmonary stabilization and diagnostic imaging with targeted interventions, such as decompressive hemicraniectomy, intracranial monitors or drains, and pharmacological agents to reduce intracranial pressure. Anesthesia and intensive care requires control of multiple physiologic variables and evidence-based practices to reduce secondary brain injury. Advances in biomedical engineering have enhanced assessments of cerebral oxygenation, pressure, metabolism, blood flow, and autoregulation. Many centers employ multimodality neuromonitoring for targeted therapies with the hope to improve recovery.

This study aimed to assess the effect of different blood pressure levels on global cerebral metabolism in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA).

In a double-blinded trial, we randomly assigned 60 comatose patients following OHCA to low (63 mmHg) or high (77 mmHg) mean arterial blood pressure (MAP). The trial was a sub-study in the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX). Global cerebral metabolism utilizing jugular bulb microdialysis (JBM) and cerebral oxygenation (rSO₂) was monitored continuously for 96 h. The lactate-to-pyruvate (LP) ratio is a marker of cellular redox status and increases during deficient oxygen delivery (ischemia, hypoxia) and mitochondrial dysfunction. The primary outcome was to compare time-averaged means of cerebral energy metabolites between MAP groups during post-resuscitation care. Secondary outcomes included metabolic patterns of cerebral ischemia, rSO₂, plasma neuron-specific enolase level at 48 h and neurological outcome at hospital discharge (cerebral performance category).

We found a clear separation in MAP between the groups (15 mmHg, p < 0.001). Cerebral biochemical variables were not significantly different between MAP groups (LPR low MAP 19 (16-31) vs. high MAP 23 (16-33), p = 0.64). However, the LP ratio remained high (> 16) in both groups during the first 30 h. During the first 24 h, cerebral lactate > 2.5 mM, pyruvate levels > 110 µM, LP ratio > 30, and glycerol > 260 µM were highly predictive for poor neurological outcome and death with AUC 0.80. The median (IQR) rSO₂ during the first 48 h was 69.5% (62.0-75.0%) in the low MAP group and 69.0% (61.3-75.5%) in the high MAP group, p = 0.16.

Among comatose patients resuscitated from OHCA, targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism within 96 h of post-resuscitation care. Patients with a poor clinical outcome exhibited significantly worse biochemical patterns, probably illustrating that insufficient tissue oxygenation and recirculation during the initial hours after ROSC were essential factors determining neurological outcome.

Cerebral microdialysis may be used in patients with severe brain injury to monitor their cerebral physiology. In this article we provide a concise synopsis with illustrations and original images of catheter types, their structure, and how they function. Where and how catheters are inserted, their identification on imaging modalities (CT and MRI), together with the roles of glucose, lactate/pyruvate ratio, glutamate, glycerol and urea are summarized in acute brain injury. The research applications of microdialysis including pharmacokinetic studies, retromicrodialysis, and its use as a biomarker for efficacy of potential therapies are outlined. Finally, we explore limitations and pitfalls of the technique, as well as potential improvements and future work that is needed to progress and expand the use of this technology.

After traumatic brain injury (TBI), cerebral metabolism can become deranged, contributing to secondary injury. Cerebral microdialysis (CMD) allows cerebral metabolism assessment and is often used with other neuro-monitoring modalities. CMD-derived parameters such as the lactate/pyruvate ratio (LPR) show a failure of oxidative energy generation. CMD-based abnormal metabolic states can be described following TBI, informing the etiology of physiological derangements. This systematic review summarizes the published literature on microdialysis-based abnormal metabolic classifications following TBI. Original research studies in which the populations were patients with TBI were included. Studies that described CMD-based classifications of metabolic abnormalities were included in the synthesis of the narrative results. A total of 825 studies underwent two-step screening after duplicates were removed. Fifty-three articles that used CMD in TBI patients were included. Of these, 14 described abnormal metabolic states based on CMD parameters. Classifications were heterogeneous between studies. LPR was the most frequently used parameter in the classifications; high LPR values were described as metabolic crisis. Ischemia was consistently defined as high LPR with low CMD substrate levels (glucose or pyruvate). Mitochondrial dysfunction, describing inability to use energy substrate despite availability, was identified based on raised LPR with near-normal levels of pyruvate. This is the first systematic review summarizing the published literature on microdialysis-based abnormal metabolic states following TBI. Although variability exists among individual classifications, there is broad agreement about broad definitions of metabolic crisis, ischemia, and mitochondrial dysfunction. Identifying the etiology of deranged cerebral metabolism after TBI is important for targeting therapeutic interventions.

Traditionally, intracranial pressure (ICP) and partial brain tissue oxygenation (PbtO₂) have been the primary invasive intracranial measurements used to guide management in patients with severe traumatic brain injury (TBI). After injury however, the brain develops an increased metabolic demand which may require an increment in the oxidative metabolism of glucose. Simultaneously, metabolic, and electrical dysfunction can lead to an inability to meet these demands, even in the absence of ischemia or increased intracranial pressure. Cerebral microdialysis provides the ability to accurately measure local concentrations of various solutes including lactate, pyruvate, glycerol and glucose. Experimental and clinical data demonstrate that such measurements of cellular metabolism can yield critical missing information about a patient's physiologic state and help limit secondary damage. Glucose management in traumatic brain injury is still an unresolved question. As cerebral glucose metabolism may be uncoupled from systemic glucose levels due to the metabolic dysfunction, measurement of cerebral extracellular glucose concentrations could provide more predictive information and prove to be a better biomarker to avoid secondary injury of at-risk brain tissue. Based on data obtained from cerebral microdialysis, specific interventions such as ICP-directed therapy, blood glucose increment, seizure control, and/or brain oxygen optimization can be instituted to minimize or prevent secondary insults. Thus, microdialysis measurements of parenchymal metabolic function provides clinically valuable information that cannot be obtained by other monitoring adjuncts in the standard ICU setting.

Cerebral microdialysis enables monitoring of brain metabolism and can be an important part of multimodal monitoring strategies in a variety of brain injuries. Microdialysis catheters can be placed in brain parenchyma through a burr hole, a cranial bolt, or directly at the time of an open craniotomy or craniectomy. The location of catheters in relation to brain pathology is important to the interpretation of data and guidance of interventions.

Here we retrospectively review the use of cerebral microdialysis at a US Regional Medical Center between March 2018 and February 2022 and provide detailed descriptions and technical nuances of the different methods to place microdialysis catheters.

Eighty two unique microdialysis catheters were utilized in 52 patients. 35 (42.68%) were placed via a quad-lumen bolt and 47 (57.32%) were placed through craniotomies. 27 catheters (32.93%) were placed in a perilesional location, 50 (60.98%) were located in healthy tissue, and 6 (7.32%) were mispositioned. No significant difference was seen between placement by bolt or craniotomy in regard to perilesional location, mispositioning, or complications.

With careful planning and thoughtful execution, cerebral microdialysis catheters can be successfully placed though a variety of strategies to optimize and individualize brain monitoring in different clinical settings. This paper provides a detailed guide for the various methods of catheter placement to help providers begin or expand their use of cerebral microdialysis.