Cerebral Physiology Research Articles

Cerebral physiologic insult burden in acute traumatic neural injury: a Canadian High Resolution-TBI (CAHR-TBI) descriptive analysis

BackgroundOver the recent decades, continuous multi-modal monitoring of cerebral physiology has gained increasing interest for its potential to help minimize secondary brain injury following moderate-to-severe acute traumatic neural injury (also termed traumatic brain injury; TBI). Despite this heightened interest, there has yet to be a comprehensive evaluation of the effects of derangements in multimodal cerebral physiology on global cerebral physiologic insult burden. In this study, we offer a multi-center descriptive analysis of the associations between deranged cerebral physiology and cerebral physiologic insult burden.MethodsUsing data from the Canadian High-Resolution TBI (CAHR-TBI) Research Collaborative, a total of 369 complete patient datasets were acquired for the purposes of this study. For various cerebral physiologic metrics, patients were trichotomized into low, intermediate, and high cohorts based on mean values. Jonckheere–Terpstra testing was then used to assess for directional relationships between these cerebral physiologic metrics and various measures of cerebral physiologic insult burden. Contour plots were then created to illustrate the impact of preserved vs impaired cerebrovascular reactivity on these relationships.ResultsIt was found that elevated intracranial pressure (ICP) was associated with more time spent with cerebral perfusion pressure (CPP) < 60 mmHg and more time with impaired cerebrovascular reactivity. Low CPP was associated with more time spent with ICP > 20 or 22 mmHg and more time spent with impaired cerebrovascular reactivity. Elevated cerebrovascular reactivity indices were associated with more time spent with CPP < 60 mmHg as well as ICP > 20 or 22 mmHg. Low brain tissue oxygenation (PbtO2) only demonstrated a significant association with more time spent with CPP < 60 mmHg. Low regional oxygen saturation (rSO2) failed to produce a statistically significant association with any particular measure of cerebral physiologic insult burden.ConclusionsMean ICP, CPP and, cerebrovascular reactivity values demonstrate statistically significant associations with global cerebral physiologic insult burden; however, it is uncertain whether measures of oxygen delivery provide any significant insight into such insult burden.

Idiopathic intracranial hypertension pathogenesis: The jugular hypothesis.

In spite of expanding research, idiopathic intracranial hypertension (IIH) and its spectrum conditions remain challenging to treat. The failure to develop effective treatment strategies is largely due to poor agreement on a coherent disease pathogenesis model. Herein we provide a hypothesis of a unifying model centered around the internal jugular veins (IJV) to explain the development of IIH, which contends the following: (1) the IJV are prone to both physiological and pathological compression throughout their course, including compression near C1 and the styloid process, dynamic muscular/carotid compression from C3 to C6, and lymphatic compression; (2) severe dynamic IJV stenosis with developments of large cervical gradients is common in IIH-spectrum patients and significantly impacts intracranial venous and cerebrospinal fluid (CSF) pressures; (3) pre-existing IJV stenosis may be exacerbated by infectious/inflammatory etiologies that induce retromandibular cervical lymphatic hypertrophy; (4) extra-jugular venous collaterals dilate with chronic use but are insufficient resulting in impaired aggregate cerebral venous outflow; (5) poor IJV outflow initiates, or in conjunction with other factors, contributes to intracranial venous hypertension and congestion leading to higher CSF pressures and intracranial pressure (ICP); (6) glymphatic congestion occurs but is insufficient to compensate and this pathway becomes overwhelmed; and (7) elevated intracranial CSF pressures triggers extramural venous sinus stenosis in susceptible individuals that amplifies ICP elevation producing severe clinical manifestations. Future studies must focus on establishing norms for dynamic cerebral venous outflow and IJV physiology in the absence of disease so that we may better understand and define the diseased state.

MR Assessment of Acute Changes of Cerebral Perfusion, Metabolism, and Blood-Brain Barrier Permeability in Response to Aerobic Exercise.

It remains unclear how a single bout of exercise affects brain perfusion, oxygen metabolism, and blood-brain barrier (BBB) permeability. Addressing this unresolved issue is essential to understand the acute changes in cerebral physiology induced by aerobic exercise. To dynamically monitor the acute changes in cerebral physiology subsequent to a single aerobic exercise training session using noninvasive MRI measurements. Prospective. Twenty-three healthy participants (18-35 years, 10 females/13 males) were enrolled and divided into 10-minute exercising (N = 10) and 20-minute exercising (N = 13) groups. 3.0 T/Phase Contrast (PC) MRI (gradient echo), T2-Relaxation-Under-Spin-Tagging (TRUST) MRI (gradient echo EPI), Water-Extraction-with-Phase-Contrast-Arterial-Spin-Tagging (WEPCAST) MRI (gradient echo EPI) and T1-weighted magnetization-prepared-rapid-acquisition-of-gradient-echo (MPRAGE) (gradient echo). A baseline MR measurement plus four repeated MR measurements immediately after 10 or 20 minutes moderate running exercise. MR measurements included cerebral blood flow (CBF) as measured by PC MRI, venous oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO2) as assessed by TRUST MRI, water extraction fraction (E), and BBB permeability-surface-area product (PS) as determined by WEPCAST MRI. The time dependence of the physiological parameters was studied with a linear mixed-effect model. Additionally, pairwise t-tests comparison of the physiological parameters at each time point was conducted. A P-value of <0.05 was considered statistically significant. There was an initial drop (8.22 ± 2.60%) followed by a recovery in CBF after exercise, while Yv revealed a significant decrease (6.37 ± 0.92%), i.e., an increased oxygen extraction, and returned to baseline at later time points. CMRO2 showed a trend of increase (5.68 ± 3.04%) and a significant interaction between time and group. In addition, E increased significantly (3.86% ± 0.89) and returned to baseline level at later time points, while PS remained elevated (13.33 ± 4.79%). A single bout of moderate aerobic exercise can induce acute alterations in cerebral perfusion, metabolism, and BBB permeability. 2 TECHNICAL EFFICACY: Stage 2.

Anesthesia for traumatic brain injury.

Traumatic brain injury (TBI) presents complex clinical challenges, requiring a nuanced understanding of its pathophysiology and current management principles to improve patient outcomes. Anesthetists play a critical role in care and need to stay updated with recent evidence and trends to ensure high-quality treatment. The Brain Trauma Foundation Guidelines, last updated in 2016, have shown moderate adherence, and much of the current management relies on expert opinions. This literature review synthesizes the current evidence and provides insights into the role of anesthetists in TBI management. Recent literature has emphasized the importance of tailored anesthetic management principles in treating TBI, focusing on minimizing secondary brain injury during neurosurgical interventions or extracranial surgery. Emerging trends include individualized intracranial pressure approaches and multimodal neuromonitoring for comprehensive assessment of cerebral physiology. Anesthesia for TBI patients requires a comprehensive approach that balances anesthetic goals with the unique pathophysiological factors of brain injury. Despite recent research expanding our understanding, challenges remain in standardizing protocols and addressing individual patient response variability. Adherence to established management principles, personalized approaches, and ongoing research is crucial for improving the outcomes.

Future of neurocritical care: Integrating neurophysics, multimodal monitoring, and machine learning

Multimodal monitoring (MMM) in the intensive care unit (ICU) has become increasingly sophisticated with the integration of neurophysical principles. However, the challenge remains to select and interpret the most appropriate combination of neuromonitoring modalities to optimize patient outcomes. This manuscript reviewed current neuromonitoring tools, focusing on intracranial pressure, cerebral electrical activity, metabolism, and invasive and noninvasive autoregulation monitoring. In addition, the integration of advanced machine learning and data science tools within the ICU were discussed. Invasive monitoring includes analysis of intracranial pressure waveforms, jugular venous oximetry, monitoring of brain tissue oxygenation, thermal diffusion flowmetry, electrocorticography, depth electroencephalography, and cerebral microdialysis. Noninvasive measures include transcranial Doppler, tympanic membrane displacement, near-infrared spectroscopy, optic nerve sheath diameter, positron emission tomography, and systemic hemodynamic monitoring including heart rate variability analysis. The neurophysical basis and clinical relevance of each method within the ICU setting were examined. Machine learning algorithms have shown promise by helping to analyze and interpret data in real time from continuous MMM tools, helping clinicians make more accurate and timely decisions. These algorithms can integrate diverse data streams to generate predictive models for patient outcomes and optimize treatment strategies. MMM, grounded in neurophysics, offers a more nuanced understanding of cerebral physiology and disease in the ICU. Although each modality has its strengths and limitations, its integrated use, especially in combination with machine learning algorithms, can offer invaluable information for individualized patient care.

Association Between Clinical Measures of Depth of Sedation and Multimodal Cerebral Physiology in Acute Traumatic Neural Injury.

Neurointensive care primarily focuses on secondary injury reduction, utilizing a variety of guideline-based approaches (including administration of high-dose sedation) to reduce the injured state. However, titration of sedation is currently based on the Richmond Agitation Sedation Scale (RASS), a subjective clinical grading score of a patient's response to external physical stimuli, and not an objective measure. Therefore, it is likely that there exists substantial variation in objective sedation depth for a given clinical grade in these patients, leading to undesired sedation depths and cerebral physiological consequences. Improper sedation can impede cerebral autoregulation, emphasizing the critical need for optimal sedation in traumatic brain injury (TBI) patients. This study evaluates the relationship between RASS to an objective measure of depth of sedation (bispectral index, BIS) and cerebral physiological measures. Fifty-nine patients were assessed using Jonckheere-Terpstra testing to compare various key physiologies with RASS. RASS (-5 through 0 categories) showed no statistically significant relationship between BIS and cerebral physiological parameters, after adjusting for multiple comparisons. Furthermore, it is crucial to note that within each RASS value, the distribution of the physiological measures all had high variability. As an exemplar, for RASS values of -5 and -4, BIS ranged from near 0 (burst suppression levels) up to over 80 (near awake states). BIS and other cerebral physiologies displayed substantial variation across each RASS category. This suggests that RASS as a means to titrate sedative medication for the goal of neuroprotection is insufficient. More momentary, individualized determination of sedation depth is required for TBI patients.

The Effect of Intermittent Pneumatic Compression on Hemodynamics and Regional Cerebral Oxygen Saturation in Laparoscopic Bariatric Surgery with Mild Hypercapnia in the Steep Reverse Trendelenburg Position.

Obesity negatively affects hemodynamics and cerebral physiology. We investigated the effect of the utilization of an intermittent pneumatic compression (IPC) device on hemodynamics and cerebral physiology in patients undergoing laparoscopic bariatric surgery under general anesthesia with lung-protective ventilation. Sixty-four patients (body mass index > 30 kg/m2) were randomly assigned to groups that received an IPC device (IPC group, n = 32) and did not (control group, n = 32). The mean arterial pressure (MAP), heart rate (HR), need for vasopressors, cerebral oxygen saturation (rSO2), and cerebral desaturation events were recorded. The incidence of intraoperative hypotension was not significantly different between groups (p = 0.153). Changes in MAP and HR over time were similar between groups (p = 0.196 and p = 0.705, respectively). The incidence of intraoperative cerebral desaturation was not significantly different between groups (p = 0.488). Changes in rSO2 over time were similar between the two groups (p = 0.190) during pneumoperitoneum. Applying IPC to patients with obesity in the steep reverse Trendelenburg position may not improve hemodynamic parameters, vasopressor requirements, or rSO2 values during pneumoperitoneum under lung-protective ventilation. During laparoscopic bariatric surgery, IPC alone has limitations in improving hemodynamics and cerebral physiology.

Identifying the Cerebral Physiologic Response to Aerobic Exercise Following Concussion: A Scoping Review.

The purpose of this study was to identify the cerebral physiologic response to aerobic exercise in individuals with a symptomatic concussion, highlighting available knowledge and knowledge gaps in the literature. A systematic scoping review was conducted and reported in keeping with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. A search of EMBASE, MEDLINE, SCOPUS, BIOSIS, and Cochrane libraries was conducted on June 15, 2023 (from database inception). An online systematic/scoping review management system was used to remove duplicates, and the remaining articles were screened for inclusion by 2 researchers. Inclusion criteria required articles to be original research published in peer-reviewed journals. Additionally, studies were required to have an aerobic exercise component, include a measure of cerebral physiology during a bout of aerobic exercise, exclude moderate and/or severe traumatic brain injury (TBI) populations, and be in the English language. Both human and animal studies were included, with participants of any age who were diagnosed with a mild TBI/concussion only (ie, Glasgow Coma Scale score ≥ 13). Studies could be of any design as long as a measure of cerebral physiologic response to a bout of aerobic exercise was included. The search resulted in 1773 articles to be screened and data from 3 eligible studies were extracted. There are currently too few studies investigating the cerebral physiologic response to aerobic exercise following concussion or mild TBI to draw definitive conclusions. Further research on this topic is necessary since understanding the cerebral physiologic response to aerobic exercise in the concussion and mild TBI populations could assist in optimizing exercise-based treatment prescription and identifying other targeted therapies.

Genetic testing for unexplained epilepsy: A review of diagnostic approach, benefits, and referral algorithm

In the last several decades, advances in genetic testing have transformed the diagnostic and therapeutic approach to pediatric epilepsy. However, the interpretation of these genetic tests often requires expert analysis and counseling. For this reason, as our molecular understanding of the linkages between abnormal cerebral physiology and genetics has grown, so too has the field of clinical epilepsy genetics. Here we explore recent advances in genetic testing, describe the benefits of genetic testing in epilepsy, and provide a practice guideline for testing and referrals to specialized epilepsy genetics centers, highlighting the Epilepsy NeuroGenetics Initiative (ENGIN) Clinic and the Center for Epilepsy and Neurodevelopmental Disorders (ENDD) at the Children's Hospital of Philadelphia as an illustration of such a specialized center.

Cerebral Microvascular Perfusion Assessed in Elderly Adults by Spin-Echo Dynamic Susceptibility Contrast MRI at 7 Tesla.

Perfusion measures of the total vasculature are commonly derived with gradient-echo (GE) dynamic susceptibility contrast (DSC) MR images, which are acquired during the early passes of a contrast agent. Alternatively, spin-echo (SE) DSC can be used to achieve specific sensitivity to the capillary signal. For an improved contrast-to-noise ratio, ultra-high-field MRI makes this technique more appealing to study cerebral microvascular physiology. Therefore, this study assessed the applicability of SE-DSC MRI at 7 T. Forty-one elderly adults underwent 7 T MRI using a multi-slice SE-EPI DSC sequence. The cerebral blood volume (CBV) and cerebral blood flow (CBF) were determined in the cortical grey matter (CGM) and white matter (WM) and compared to values from the literature. The relation of CBV and CBF with age and sex was investigated. Higher CBV and CBF values were found in CGM compared to WM, whereby the CGM-to-WM ratios depended on the amount of largest vessels excluded from the analysis. CBF was negatively associated with age in the CGM, while no significant association was found with CBV. Both CBV and CBF were higher in women compared to men in both CGM and WM. The current study verifies the possibility of quantifying cerebral microvascular perfusion with SE-DSC MRI at 7 T.

Association of RAP Compensatory Reserve Index with Continuous Multimodal Monitoring Cerebral Physiology, Neuroimaging, and Patient Outcome in Adult Acute Traumatic Neural Injury: A Scoping Review.

Acute traumatic neural injury, known as traumatic brain injury (TBI), stands as a significant contributor to global mortality and disability. Ideally, continuously monitoring cerebral compliance/cerebral compensatory reserve would enable timely interventions and avert further substantial deterioration in TBI cases. RAP, defined as the moving Pearson's correlation between intracranial pressure (ICP) pulse amplitude waveform and ICP, has been proposed as a continuously updating index in this context. However, the literature remains scattered and difficult to navigate. Thus, the goal of this scoping review was to comprehensively characterize the literature regarding RAP and its association with (1) other multimodal cerebral physiological monitoring, (2) neuroimaging features, and (3) long-term patient outcomes. We subsequently conducted a systematic scoping review of the human literature to highlight the association of RAP with continuous multimodal monitoring of cerebral physiology, neuroimaging, and patient outcomes in the context of adult TBI patients. Our review encompassed 21 studies focusing on these topics. The primary findings involve meticulous analysis of studies, categorizing findings into three states of RAP to clearly understand its relation to cerebral physiology and clinical outcomes. State 1 signifies a healthy condition with a small positive value near zero (RAP <0.5). Conversely, state 2, a predominant characterization of TBI patients, indicates compromised compensatory reserve, featuring a large positive RAP value (RAP > 0.4). State 3 emerges in worsened conditions, showcasing further compromised compensatory reserve, exhausted cerebrovascular reactivity, and disturbed cerebral autoregulation. A substantial number of patients with fatal outcomes was found in state 3, marked by a notable occurrence of decreasing and, in some instances, negative RAP. The significance of this review lies in establishing a platform for future research directions to enhance the precision and clinical implications of RAP in TBI care, ultimately aiming to prevent the transition from state 2 to state 3 and mitigate fatal outcomes.

Cerebral perfusion simulation using realistically generated synthetic trees for healthy and stroke patients

Background and objectiveCerebral vascular diseases are among the most burdensome diseases faced by society. However, investigating the pathophysiology of diseases as well as developing future treatments still relies heavily on expensive in-vivo and in-vitro studies. The generation of realistic, patient-specific models of the cerebrovascular system capable of simulating hemodynamics and perfusion promises the ability to simulate diseased states, therefore accelerating development cycles using in silico studies and opening opportunities for the individual assessment of diseased states, treatment planning, and the prediction of outcomes. By providing a patient-specific, anatomically detailed and validated model of the human cerebral vascular system, we aim to provide the basis for future in silico investigations of the cerebral physiology and pathology. MethodsIn this retrospective study, a processing pipeline for patient-specific quantification of cerebral perfusion was developed and applied to healthy individuals and a stroke patient. Major arteries are segmented from 3T MR angiography data. A synthetic tree generation algorithm titled tissue-growth based optimization (GBO)1 is used to extend vascular trees beyond the imaging resolution. To investigate the anatomical accuracy of the generated trees, morphological parameters are compared against those of 7 T MRI, 9.4 T MRI, and dissection data. Using the generated vessel model, hemodynamics and perfusion are simulated by solving one-dimensional blood flow equations combined with Darcy flow equations. ResultsMorphological data of three healthy individuals (mean age 47 years ± 15.9 [SD], 2 female) was analyzed. Bifurcation and physiological characteristics of the synthetically generated vessels are comparable to those of dissection data. The inability of MRI based segmentation to resolve small branches and the small volume investigated cause a mismatch in the comparison to MRI data. Cerebral perfusion was estimated for healthy individuals and a stroke patient. The simulated perfusion is compared against Arterial-Spin-Labeling MRI perfusion data. Good qualitative agreement is found between simulated and measured cerebral blood flow (CBF)2. Ischemic regions are predicted well, however ischemia severity is overestimated. ConclusionsGBO successfully generates detailed cerebral vascular models with realistic morphological parameters. Simulations based on the resulting networks predict perfusion territories and ischemic regions successfully.

The Effect of Tucaresol on Translational MRI Estimates of Cerebral Physiology in Townes SCD Mice

Sickle Cell Disease (SCD) is characterized by severe hemolytic anemia and low Hct. This contributes to elevated cerebral cerebrometabolic strain, as evidenced by increased cerebral blood flow (CBF), increased blood oxygen extraction fraction (OEF), and increased incidence of silent cerebral infarct. Recent reports have shown that approved and experimental therapies ameliorate these physiological indicators of strain in SCD patients using advanced MRI-based techniques (Fields, et al., Blood, 2019; Hulbert, et al., Blood 2022), but the effect on these same MRI endpoints has not been demonstrated in animal models of SCD. The purpose of this work was to perform these same measurements in Townes SCD mice treated with tucaresol, which is known to increase the oxygen affinity hemoglobin, thus building a translational platform for non-invasive assessment of these endpoints to support characterization of novel therapies and their relationship to cerebrometabolic strain that leads to end organ damage in the brain. All animal procedures were performed under an IACUC-approved protocol. Forty-three male Townes SCD mice were assigned to two treatment groups (n=21 / 22, mean age = 8.1±0.8 / 8.4 ±0.6 weeks, mean weight = 26±2 / 26±2 g). Animals were anesthetized and scanned on a 9.4 T Bruker MRI scanner at MGH. CBF was measured using a pseudo-continuous arterial spin labeling sequence (pCASL) (Hirschler, et al., NMR in Biomedicine, 2018), and OEF was estimated from a T2 measurement in the superior sagittal sinus using a TRUST sequence (Wei, et al., Magn. Reson. Med., 2018) and a hematocrit measure which was taken from a tail vein bleed immediately following the scan. Following anesthesia recovery from the first imaging timepoint, animals were placed in cages according to group assignment and drinking water was replaced by one of two masked dosing solutions. prepared off-site by an independent team, containing either 1.14 mM tucaresol or pH and color-matched water. The tucaresol concentration was chosen to approximate an oral dose of 60 mg/kg/day comparable to a clinical dose and be consistent with previous studies. After two weeks of ad lib exposure to the dosing solutions, the scanning and blood sampling procedure was repeated. A terminal cardiac punch was also performed under anesthesia to assess tucaresol blood exposure. Due to technical challenges Hct measures were not performed in the first five animals from each group, and two animals had Hct measures at only the second timepoint. CBF is reported in whole bilateral striatum. Whole blood analysis revealed tucaresol exposures of 0.1-0.6 mM in the active arm. While still within the range for hemoglobin modification, the exposures were similar but somewhat lower than the exposures of 0.5-1.6 mM reported from oral gavage at 30 mg/kg twice per day in SCD mice (Knee et al. Blood, 2016). Table 1 shows CBF, Hct, and OEF values at baseline and after two weeks of dosing for each group. OEF values assume arterial oxygen saturation of 1. Spaghetti plots in figure 1 display changes in these values for individual animals. CBF elevations are observed very early in clinical SCD populations and begin to plateau as the disease progresses, but OEF has been shown to increase as the disease progresses (Juttukunda, et al., J. Magn. Reson. Imaging, 2019). As a result, therapeutic interventions in advanced disease may be expected to first affect OEF, with decreases in CBF to follow. That may, in part explain why a treatment effect was observed with OEF and not with CBF. Additionally, the proximity of the labeling plane of inflowing arterial blood to the brain tissue being perfused and the high carotid artery flow rate in these animals means that the CBF measure by pCASL MRI is considerably more challenging in mice than in humans. The sensitivity of MRI-derived OEF to therapeutic intervention in mice is similar to what has been reported in SCD patients, where elevated OEF is particularly associated with regions of the brain at highest risk for developing silent infarct. CBF and OEF are currently being evaluating for an approved HbS modifier (NCT05228821). The ability to use the same techniques in both mice and humans to non-invasively and quantitatively demonstrate the amelioration of the cerebrophysiological compensatory measures that precede end CNS organ damage is a valuable step in characterizing potential benefit of novel therapeutics beyond standard regulatory endpoints associated with pain crises.

Correlation and asynchronization of electroencephalogram and cerebral blood flow in active and passive stimulations

Objective. Real-time brain monitoring is of importance for intraoperative surgeries and intensive care unit, in order to take timely clinical interventions. Electroencephalogram (EEG) is a conventional technique for recording neural excitations (e.g. brain waves) in the cerebral cortex, and near infrared diffuse correlation spectroscopy (DCS) is an emerging technique that can directly measure the cerebral blood flow (CBF) in microvasculature system. Currently, the relationship between the neural activities and cerebral hemodynamics that reflects the vasoconstriction features of cerebral vessels, especially under both active and passive situation, has not been elucidated thus far, which triggers the motivation of this study. Approach. We used the verbal fluency test as an active cognitive stimulus to the brain, and we manipulated blood pressure changes as a passive challenge to the brain. Under both protocols, the CBF and EEG responses were longitudinally monitored throughout the cerebral stimulus. Power spectrum approaches were applied the EEG signals and compared with CBF responses. Main results. The results show that the EEG response was significantly faster and larger in amplitude during the active cognitive task, when compared to the CBF, but with larger individual variability. By contrast, CBF is more sensitive when response to the passive task, and with better signal stability. We also found that there was a correlation (p < 0.01, r = 0.866, R 2 = 0.751) between CBF and EEG in initial response during the active task, but no significant correlation (p > 0.05) was found during the passive task. The similar relations were also found between regional brain waves and blood flow. Significance. The asynchronization and correlation between the two measurements indicates the necessity of monitoring both variables for comprehensive understanding of cerebral physiology. Deep exploration of their relationships provides promising implications for DCS/EEG integration in the diagnosis of various neurovascular and psychiatric diseases.

Patients with type 1 diabetes and albuminuria have a reduced brain glycolytic capability that is correlated with brain atrophy.

Patients with type 1 diabetes (T1D) demonstrate brain alterations, including white matter lesions and cerebral atrophy. In this case-control study, we investigated if a reason for this atrophy could be because of diabetes-related complications affecting cerebrovascular or cerebral glycolytic functions. Cerebral physiological dysfunction can lead to energy deficiencies and, consequently, neurodegeneration. We examined 33 patients with T1D [18 females, mean age: 50.8 years (range: 26-72)] and 19 matched healthy controls [7 females, mean age: 45.0 years (range: 24-64)]. Eleven (33%) of the patients had albuminuria. Total brain volume, brain parenchymal fraction, gray matter volume and white matter volume were measured by anatomical MRI. Cerebral vascular and glycolytic functions were investigated by measuring global cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral lactate concentration in response to the inhalation of hypoxic air (12-14% fractional oxygen) using phase-contrast MRI and magnetic resonance spectroscopy (MRS) techniques. The inspiration of hypoxic air challenges both cerebrovascular and cerebral glycolytic physiology, and an impaired response will reveal a physiologic dysfunction. Patients with T1D and albuminuria had lower total brain volume, brain parenchymal fraction, and gray matter volume than healthy controls and patients without albuminuria. The inhalation of hypoxic air increased CBF and lactate in all groups. Patients with albuminuria had a significantly (p = 0.032) lower lactate response compared to healthy controls. The CBF response was lower in patients with albuminuria compared to healthy controls, however not significantly (p = 0.24) different. CMRO2 was unaffected by the hypoxic challenge in all groups (p > 0.16). A low lactate response was associated with brain atrophy, characterized by reduced total brain volume (p = 0.003) and reduced gray matter volume (p = 0.013). We observed a reduced response of the lactate concentration as an indication of impaired glycolytic activity, which correlated with brain atrophy. Inadequacies in upregulating cerebral glycolytic activity, perhaps from reduced glucose transporters in the brain or hypoxia-inducible factor 1 pathway dysfunction, could be a complication in diabetes contributing to the development of neurodegeneration and declining brain health.

Proteomic Analyses Reveal Functional Pathways and Potential Targets in Pediatric Hydrocephalus.

Hydrocephalus is a common pediatric disorder of cerebral spinal fluid physiology resulting in abnormal expansion of the cerebral ventricles. However, the underlying molecular mechanisms remain unknown. We performed proteomic analyses of cerebrospinal fluid (CSF) from 7 congenital hydrocephalus and 5 arachnoid cyst patients who underwent surgical treatment. Differentially expressed proteins (DEPs) were identified by label-free Mass Spectrometry followed by differential expression analysis. The GO and GSEA enrichment analysis was performed to explore the cancer hallmark pathways and immune-related pathways affected by DEPs. Then, network analysis was applied to reveal the location of DEPs in the human protein-protein interactions (PPIs) network. Potential drugs for hydrocephalus were identified based on drug-target interaction. We identified 148 up-regulated proteins and 82 down-regulated proteins, which are potential biomarkers for clinical diagnosis of hydrocephalus and arachnoid cyst. Functional enrichment analysis revealed that the DEPs were significantly enriched in the cancer hallmark pathways and immunerelated pathways. In addition, network analysis uncovered that DEPs were more likely to be located in the central regions of the human PPIs network, suggesting DEPs may be proteins that play important roles in human PPIs. Finally, we calculated the overlap of drug targets and the DEPs based on drugtarget interaction to identify the potential therapeutic drugs of hydrocephalus. The comprehensive proteomic analyses provided valuable resources for investigating the molecular pathways in hydrocephalus, and uncovered potential biomarkers for clinical diagnosis and therapy.

Toward translating novel imaging biomarkers from preclinical to clinical settings

Microvascular imaging of the neonatal brain is now feasible with the advent of ultrasound technologies that enable detection of slow flow in smaller vessels. As an advancement from conventional Doppler, microvascular imaging (MVI) technique has been applied in neonatal brain ultrasound scans to better understand how anatomic and functional changes of cerebral microvessels relate to disease diagnostics and prognosis in the neonatal brain. This lecture will introduce about the technique, current and emerging applications of MVI, as well as challenges and future directions of advancing cerebral microvascular markers of neonatal brain health. Some of the invasive methods used to study cerebral physiology and biomarkers in high-fidelity preclinical models are difficult to directly test and validate in vulnerable neonates. As such, this lecture will open up the forum for future directions on how the scientific and medical fields can come together in advancing the clinical validation and integration of novel imaging biomarkers to improve neonatal brain health.

Reproducibility of cerebral blood flow, oxygen metabolism, and lactate and N-acetyl-aspartate concentrations measured using magnetic resonance imaging and spectroscopy.

In humans, resting cerebral perfusion, oxygen consumption and energy metabolism demonstrate large intersubject variation regardless of methodology. Whether a similar large variation is also present longitudinally in individual subjects is much less studied, but knowing the time variance in reproducibility is important when designing and interpreting longitudinal follow-up studies examining brain physiology. Therefore, we examined the reproducibility of cerebral blood flow (CBF), global cerebral metabolic rate of oxygen (CMRO2), global arteriovenous oxygen saturation difference (A-V.O2), and cerebral lactate and N-acetyl-aspartate (NAA) concentrations measured using magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques through repeated measurements at 6h, 24h, 7days and several weeks after initial baseline measurements in young healthy adults (N = 26, 13 females, age range 18-35years). Using this setup, we calculated the correlation, limit of agreement (LoA) and within-subject coefficient of variation (CoVWS) between baseline values and the subsequent repeated measurements to examine the longitudinal variation in individual cerebral physiology. CBF and CMRO2 correlated significantly between baseline and all subsequent measurements. The strength of the correlations (R2) and reproducibility metrics (LoA and CoVWS) demonstrated the best reproducibility for the within-day measurements and generally declined with longer time between measurements. Cerebral lactate and NAA concentrations also correlated significantly for all measurements, except between baseline and the 7-day measurement for lactate. Similar to CBF and CMRO2, lactate and NAA demonstrated the best reproducibility for within-day repeated measurements. The gradual decline in reproducibility over time should be considered when designing and interpreting studies on brain physiology, for example, in the evaluation of treatment efficacy.

Brain tissue oxygen monitoring in traumatic brain injury: part I—To what extent does PbtO2 reflect global cerebral physiology?

BackgroundThe primary aim was to explore the association of global cerebral physiological variables including intracranial pressure (ICP), cerebrovascular reactivity (PRx), cerebral perfusion pressure (CPP), and deviation from the PRx-based optimal CPP value (∆CPPopt; actual CPP-CPPopt) in relation to brain tissue oxygenation (pbtO2) in traumatic brain injury (TBI).MethodsA total of 425 TBI patients with ICP- and pbtO2 monitoring for at least 12 h, who had been treated at the neurocritical care unit, Addenbrooke’s Hospital, Cambridge, UK, between 2002 and 2022 were included. Generalized additive models (GAMs) and linear mixed effect models were used to explore the association of ICP, PRx, CPP, and CPPopt in relation to pbtO2. PbtO2 < 20 mmHg, ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, and ∆CPPopt < − 5 mmHg were considered as cerebral insults.ResultsPbtO2 < 20 mmHg occurred in median during 17% of the monitoring time and in less than 5% in combination with ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, or ∆CPPopt < − 5 mmHg. In GAM analyses, pbtO2 remained around 25 mmHg over a large range of ICP ([0;50] mmHg) and PRx [− 1;1], but deteriorated below 20 mmHg for extremely low CPP below 30 mmHg and ∆CPPopt below − 30 mmHg. In linear mixed effect models, ICP, CPP, PRx, and ∆CPPopt were significantly associated with pbtO2, but the fixed effects could only explain a very small extent of the pbtO2 variation.ConclusionsPbtO2 below 20 mmHg was relatively frequent and often occurred in the absence of disturbances in ICP, PRx, CPP, and ∆CPPopt. There were significant, but weak associations between the global cerebral physiological variables and pbtO2, suggesting that hypoxic pbtO2 is often a complex and independent pathophysiological event. Thus, other variables may be more crucial to explain pbtO2 and, likewise, pbtO2 may not be a suitable outcome measure to determine whether global cerebral blood flow optimization such as CPPopt therapy is successful.

Evaluating Physiological MRI Parameters in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery-A Preliminary Analysis and Case Report.

Brain metastases occur in ten to thirty percent of the adult cancer population. Treatment consists of different (palliative) options, including stereotactic radiosurgery (SRS). Sensitive MRI biomarkers are needed to better understand radiotherapy-related effects on cerebral physiology and the subsequent effects on neurocognitive functioning. In the current study, we used physiological imaging techniques to assess cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2) and cerebrovascular reactivity (CVR) before and three months after SRS in nine patients with brain metastases. The results showed improvement in OEF, CBF and CMRO2 within brain tissue that recovered from edema (all p ≤ 0.04), while CVR remained impacted. We observed a global post-radiotherapy increase in CBF in healthy-appearing brain tissue (p = 0.02). A repeated measures correlation analysis showed larger reductions within regions exposed to higher radiotherapy doses in CBF (rrm = -0.286, p < 0.001), CMRO2 (rrm = -0.254, p < 0.001), and CVR (rrm = -0.346, p < 0.001), but not in OEF (rrm = -0.004, p = 0.954). Case analyses illustrated the impact of brain metastases progression on the post-radiotherapy changes in both physiological MRI measures and cognitive performance. Our preliminary findings suggest no radiotherapy effects on physiological parameters occurred in healthy-appearing brain tissue within 3-months post-radiotherapy. Nevertheless, as radiotherapy can have late side effects, larger patient samples allowing meaningful grouping of patients and longer follow-ups are needed.