Neuroimaging evaluation of the long term impact of a novel paired meditation practice on brain function.

Background: A growing number of advanced neuroimaging studies have compared brain structure and function in long term meditators to non-meditators. The goal is to determine if there may be long term effects on the brain from practicing meditation. In this paper, we present new data on the long term effects of a novel meditation practice in which the focus is on clitoral stimulation. The findings from such a study have implications for potential therapeutic uses with regard to various neurological or psychiatric conditions. Methods: We evaluated the cerebral glucose metabolism in 40 subjects with an extended history (>1 year of practice, 2-3 times per week) performing the meditation practice called Orgasmic Meditation (OM) and compared their brains to a group of non-meditating healthy controls (N = 19). Both meditation and non-meditation subjects underwent brain PET after injection with 148 to 296 MBq of FDG using a standard imaging protocol. Resting FDG PET scans of the OM group were compared to the resting scans of healthy, non-meditating, controls using statistical parametric mapping. Results: The OM group showed significant differences in metabolic activity at rest compared to the controls. Specifically, there was significantly lower metabolism in select areas of the frontal, temporal, and parietal lobes, as well as the anterior cingulate, insula, and thalamus, in the OM group compared to the controls. In addition, there were notable distinctions between the males and females with the females demonstrating significantly lower metabolism in the thalamus and insula. Conclusions: Overall, these findings suggest that the long term meditation practitioners of OM have different patterns of resting brain metabolism. Since these areas of the brain in which OM practitioners differ from controls are involved in cognition, attention, and emotional regulation, such findings have implications for understanding how this meditation practice might affect practitioners over long periods of time.

Ketone Bodies after Cardiac Arrest: A Narrative Review and the Rationale for Use.

Cardiac arrest survivors suffer the repercussions of anoxic brain injury, a critical factor influencing long-term prognosis. This injury is characterised by profound and enduring metabolic impairment. Ketone bodies, an alternative energetic resource in physiological states such as exercise, fasting, and extended starvation, are avidly taken up and used by the brain. Both the ketogenic diet and exogenous ketone supplementation have been associated with neuroprotective effects across a spectrum of conditions. These include refractory epilepsy, neurodegenerative disorders, cognitive impairment, focal cerebral ischemia, and traumatic brain injuries. Beyond this, ketone bodies possess a plethora of attributes that appear to be particularly favourable after cardiac arrest. These encompass anti-inflammatory effects, the attenuation of oxidative stress, the improvement of mitochondrial function, a glucose-sparing effect, and the enhancement of cardiac function. The aim of this manuscript is to appraise pertinent scientific literature on the topic through a narrative review. We aim to encapsulate the existing evidence and underscore the potential therapeutic value of ketone bodies in the context of cardiac arrest to provide a rationale for their use in forthcoming translational research efforts.

Age-related decline in cerebral oxygen consumption in multiple sclerosis.

Cerebral oxygen metabolism is altered in relapsing-remitting multiple sclerosis (RRMS), possibly a result of disease related cerebral atrophy with subsequent decreased oxygen demand. However, MS inflammation can also inhibit brain metabolism. Therefore, we measured cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) using MRI phase contrast mapping and susceptibility-based oximetry in 44 patients with early RRMS and 36 healthy controls. Cerebral atrophy and white matter lesion load were assessed from high-resolution structural MRI. Expanded Disability Status Scale (EDSS) scores were collected from medical records. The CMRO2 was significantly lower in patients (-15%, p = 0.002) and decreased significantly with age in patients relative to the controls (-1.35 µmol/100 g/min/year, p = 0.036). The lower CMRO2 in RRMS was primarily driven by a higher venous oxygen saturation in the sagittal sinus (p = 0.007) and not a reduction in CBF (p = 0.69). There was no difference in cerebral atrophy between the groups, and no correlation between CMRO2 and MS lesion volume or EDSS score. Therefore, the progressive CMRO2 decline observed before the occurrence of significant cerebral atrophy and despite adequate CBF supports emerging evidence of dysfunctional cellular respiration as a potential pathogenic mechanism and therapeutic target in RRMS.

On the coupling and decoupling of mind wandering and perception: a shared metabolism account.

Introduction: Mind wandering (MW) has been associated with reduced responsiveness to external stimuli ("perceptual decoupling"). Conversely, increased perceptual demands of a task result in reduced MW. Here we propose a neurobiological account attributing the mutually-limiting relationship of MW and perception to brain-wide limits on cerebral metabolism. Since overall cerebral metabolism is known to remain constant, despite increased mental task demands, we tested whether increased perceptual processing load in a visual task will result in reduced oxygen metabolism in MW-related medial prefrontal cortex (mPFC) regions. Methods: We used broadband near-infrared spectroscopy to measure oxidation states of the cytochrome-c-oxidase enzyme (oxCCO), an intracellular marker of metabolism, in mPFC while sampling participants' MW experiences during their performance of a visual task of either low (feature search) or high(conjunction search) perceptual load. Results: Increased perceptual load in the task resulted in reduced oxCCO signal in mPFC regions related to MW reports. High perceptual load was also found to specifically suppress detailed (and hence more metabolism-demanding) rather than vague MW. Discussion: Overall, the results support a shared metabolism account of the relationship between MW and perception and demonstrate that attentional-regulation of metabolism only supports ongoing detailed MW when perceptual processing demands are low.

Quantification of pyruvate in-vitro using mid-infrared spectroscopy: Developing a system for microdialysis monitoring in traumatic brain injury patients.

Introduction: 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. Research question: 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. Materials and methods: 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. Results: We characterised the system to extract its relevant figures-of-merit and report the LOD of 0.07 mM. Discussion and conclusion: 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.

Cerebrospinal fluid analysis of metabolites is not correlated to microdialysis measurements in acute brain injured patients.

BACKGROUND: Cerebral microdialysis (CMD) has become an established bedside monitoring modality but its implementation remains complex and costly and is therefore performed only in a few well-trained academic centers. This study investigated the relationship between cerebrospinal fluid (CSF) and CMD glucose and lactate concentrations. METHODS: Two centers retrospective study of prospectively collected data. Consecutive adult (>18 years) acutely brain injured patients admitted to the Intensive Care Unit between 2010 and 2021 were eligible if CSF and CMD glucose and lactate concentrations were concomitantly measured at least once. RESULTS: Of 113 patients being monitored with an external ventricular drainage and CMD, 49 patients (25 from Innsbruck and 24 from Brussels) were eligible for the final analysis, including a total of 96 measurements. Median CMD glucose and lactate concentrations were 1.15 (0.51-1.57) mmol/L and 3.44 (2.24-5.37) mmol/L, respectively; median CSF glucose and lactate concentrations were 4.67 (4.03-5.34) mmol/L and 3.40 (2.85-4.10) mmol/L, respectively. For the first measurements, no correlation between CSF and CMD glucose concentrations (R2 <0.01; p = 0.95) and CSF and CMD lactate concentrations (R2 =0.16; p = 0.09) was found. Considering all measurements, the repeated measure correlation analysis also showed no correlation for glucose (rrm = -0.01; 95% Confidence Intervals -0.306 to 0.281; p = 0.93) and lactate (rrm = -0.11; 95% Confidence Intervals -0.424 to 0.236; p = 0.55). CONCLUSIONS: In this study including acute brain injured patients, no correlation between CSF and brain tissue measurements of glucose and lactate was observed. As such, CSF measurements of such metabolites cannot replace CMD findings.

Cerebrovascular reactivity to carbon dioxide tension in newborns: data from combined time-resolved near-infrared spectroscopy and diffuse correlation spectroscopy.

Significance: Critically ill newborns are at risk of brain damage from cerebrovascular disturbances. A cerebral hemodynamic monitoring system would have the potential role to guide targeted intervention. Aim: To obtain, in a population of newborn infants, simultaneous near-infrared spectroscopy (NIRS)-based estimates of cerebral tissue oxygen saturation (StO2) and blood flow during variations of carbon dioxide tension (pCO2) levels within physiologic values up to moderate permissive hypercapnia, and to examine if the derived estimate of metabolic rate of oxygen would stay constant, during the same variations. Approach: We enrolled clinically stable mechanically ventilated newborns at postnatal age >24 h without brain abnormalities at ultrasound. StO2 and blood flow index were measured using a non-invasive device (BabyLux), which combine time-resolved NIRS and diffuse-correlation spectroscopy. The effect of changes in transcutaneous pCO2 on StO2, cerebral blood flow (CBF), and cerebral metabolic rate of oxygen index (tCMRO2i) were estimated. Results: Ten babies were enrolled and three were excluded. Median GA at enrollment was 39 weeks and median weight 2720 g. StO2 increased 0.58% (95% CI 0.55; 0.61, p<0.001), CBF 2% (1.9; 2.3, p<0.001), and tCMRO2 0.3% (0.05; 0.46, p=0.017) per mmHg increase in pCO2. Conclusions: BabyLux device detected pCO2-induced changes in cerebral StO2 and CBF, as expected. The small statistically significant positive relationship between pCO2 and tCMRO2i variation is not considered clinically relevant and we are inclined to consider it as an artifact.

Investigating the link between regional oxygen metabolism and cognitive speed in multiple sclerosis: Implications for fatigue.

BACKGROUND: Most multiple sclerosis (MS) patients experience fatigue and cognitive decline but the underlying mechanisms remain unknown. Previous work has shown whole brain resting cerebral metabolic rate of oxygen (CMRO2) is associated with the extent of these symptoms. However, it is not known if the association between global CMRO2 and MS-related cognitive speed and fatigue can be localized to specific brain regions. Based upon previous research suggesting prefrontal involvement in MS-related changes in cognitive speed and fatigue, we hypothesized that oxygen metabolic changes within prefrontal cortex (PFC) might form the pathophysiologic basis of cognitive performance and fatigue in MS patients. OBJECTIVE: Investigate whether PFC ΔCMRO2 is associated with cognitive speed and fatigue in MS. METHODS: MS and healthy control (HC) participants were scanned using a dual--echo fMRI sequence and underwent a hypercapnia calibration experiment that permitted estimation of ΔCMRO2 while performing a scanner version of symbol-digit modalities task, a measure of information processing speed and utilized in the clinic as a reliable sentinel biomarker for global cognitive impairment in MS. Participants then completed the Modified Fatigue Impact Scale (MFIS) to measure fatigue. RESULTS: MS patients exhibited significant reductions in cognitive performance relative to HCs (p < 0.04). Prefrontal ΔCMRO2 explained significant variability (ΔR2 = 0.11) in cognitive speed, over and above disease and demographic variables, for the MS group only. Prefrontal ΔCMRO2 was not associated with fatigue across groups. ΔCMRO2 in visual and motor areas were not associated with cognitive performance or fatigue for either group. CONCLUSION: Prefrontal oxygen metabolism may be a sensitive measure of MS-related cognitive decline.

Alterations in rat brain modular organization during unconsciousness are dependent on communication efficiency and metabolic cost.

Spontaneous brain activity exhibits a highly structured modular organization that varies across individuals and reconfigures over time. Although it has been proposed that brain organization is shaped by an economic trade-off between minimizing costs and facilitating efficient information transfer, it remains untested whether modular variability and its changes during unconscious conditions might be constrained by the economy of brain organization. We acquired functional MRI and FDG-PET in rats under three different levels of consciousness induced by propofol administration. We examined alterations in brain modular variability during loss of consciousness from mild sedation to deep anesthesia. We also investigated the relationships between modular variability with glucose metabolism and functional connectivity strength as well as their alterations during unconsciousness. We observed that modular variability increased during loss of consciousness. Critically, across-individual modular variability is oppositely associated with functional connectivity strength and cerebral metabolism, and with deepening dosage of anesthesia, becoming increasingly dependent on basal metabolism over functional connectivity. These results suggested that, propofol-induced unconsciousness may lead to brain modular reorganization, which are putatively shaped by re-negotiations between energetic resources and communication efficiency.

Early changes in cerebral metabolism after perinatal hypoxia-ischemia: a study in normothermic and hypothermic piglets.

Introduction: Hypoxic ischemic encephalopathy (HIE) after a perinatal insult is a dynamic process that evolves over time. Therapeutic hypothermia (TH) is standard treatment for severe to moderate HIE. There is a lack of evidence on the temporal change and interrelation of the underlying mechanisms that constitute HIE under normal and hypothermic conditions. We aimed to describe early changes in intracerebral metabolism after a hypoxic-ischemic insult in piglets treated with and without TH and in controls. Methods: Three devices were installed into the left hemisphere of 24 piglets: a probe measuring intracranial pressure, a probe measuring blood flow and oxygen tension, and a microdialysis catheter measuring lactate, glucose, glycerol, and pyruvate. After a standardized hypoxic ischemic insult, the piglets were randomized to either TH or normothermia. Results: Glycerol, a marker of cell lysis, increased immediately after the insult in both groups. There was a secondary increase in glycerol in normothermic piglets but not in piglets treated with TH. Intracerebral pressure, blood flow, oxygen tension, and extracellular lactate remained stable during the secondary increase in glycerol. Conclusion: This exploratory study depicted the development of the pathophysiological mechanisms in the hours following a perinatal hypoxic-ischemic insult with and without TH and controls.

Multimodal monitoring: practical recommendations (dos and don'ts) in challenging situations and uncertainty.

With the advancements in modern medicine, new methods are being developed to monitor patients in the intensive care unit. Different modalities evaluate different aspects of the patient's physiology and clinical status. The complexity of these modalities often restricts their use to the realm of clinical research, thereby limiting their use in the real world. Understanding their salient features and their limitations can aid physicians in interpreting the concomitant information provided by multiple modalities to make informed decisions that may affect clinical care and outcomes. Here, we present a review of the commonly used methods in the neurological intensive care unit with practical recommendations for their use.

The effect of neuroinflammation on the cerebral metabolism at baseline and after neural stimulation in neurodegenerative diseases.

Neuroinflammation is a reaction of nervous tissue to an attack caused by an infection, a toxin, or a neurodegenerative disease. It involves brain metabolism adaptation in order to meet the increased energy needs of glial cell activation, but the nature of these adaptations is still unknown. Increasing interest concerning neuroinflammation leads to the identification of its role in neurodegenerative diseases. Few reports studied the effect of metabolic alteration on neuroinflammation. Metabolic damage initiates a pro-inflammatory response by microglial activation. Moreover, the exact neuroinflammation effect on cerebral cell metabolism remains unknown. In this study, we reviewed systematically the neuroinflammation effect in animal models' brains. All articles showing the relationship of neuroinflammation with brain metabolism, or with neuronal stimulation in neurodegenerative diseases were considered. Moreover, this review examines also the mitochondrial damage effect in neurodegeneration diseases. Then, different biosensors are classified regarding their importance in the determination of metabolite change. Finally, some therapeutic drugs inhibiting neuroinflammation are cited. Neuroinflammation increases lymphocyte infiltration and cytokines' overproduction, altering cellular energy homeostasis. This review demonstrates the importance of neuroinflammation as a mediator of disease progression. Further, the spread of depolarization effects pro-inflammatory genes expression and microglial activation, which contribute to the degeneration of neurons, paving the road to better management and treatment of neurodegenerative diseases.

Multinuclear Magnetic Resonance Spectroscopy at Ultra-High-Field: Assessing Human Cerebral Metabolism in Healthy and Diseased States.

The brain is a highly energetic organ. Although the brain can consume metabolic substrates, such as lactate, glycogen, and ketone bodies, the energy metabolism in a healthy adult brain mainly relies on glucose provided via blood. The cerebral metabolism of glucose produces energy and a wide variety of intermediate metabolites. Since cerebral metabolic alterations have been repeatedly implicated in several brain disorders, understanding changes in metabolite levels and corresponding cell-specific neurotransmitter fluxes through different substrate utilization may highlight the underlying mechanisms that can be exploited to diagnose or treat various brain disorders. Magnetic resonance spectroscopy (MRS) is a noninvasive tool to measure tissue metabolism in vivo. 1H-MRS is widely applied in research at clinical field strengths (≤3T) to measure mostly high abundant metabolites. In addition, X-nuclei MRS including, 13C, 2H, 17O, and 31P, are also very promising. Exploiting the higher sensitivity at ultra-high-field (>4T; UHF) strengths enables obtaining unique insights into different aspects of the substrate metabolism towards measuring cell-specific metabolic fluxes in vivo. This review provides an overview about the potential role of multinuclear MRS (1H, 13C, 2H, 17O, and 31P) at UHF to assess the cerebral metabolism and the metabolic insights obtained by applying these techniques in both healthy and diseased states.

A randomized, double-blind trial comparing the effect of two blood pressure targets on global brain metabolism after out-of-hospital cardiac arrest.

PURPOSE: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Alteration in Cerebral Metabolism in a Rodent Model of Acute Sub-lethal Cyanide Poisoning.

INTRODUCTION: Cyanide exposure can occur in various settings such as industry and metallurgy. The primary mechanism of injury is cellular hypoxia from Complex IV (CIV) inhibition. This leads to decreased ATP production and increased reactive oxygen species production. The brain and the heart are the organs most affected due to their high metabolic demand. While the cardiac effects of cyanide are well known, the cerebral effects on cellular function are less well described. We investigated cerebral metabolism with a combination of brain respirometry, microdialysis, and western blotting using a rodent model of sub-lethal cyanide poisoning. METHODS: Twenty rodents were divided into two groups: control (n = 10) and sub-lethal cyanide (n = 10). Cerebral microdialysis was performed during a 2 mg/kg/h cyanide exposure to obtain real-time measurements of cerebral metabolic status. At the end of the exposure (90 min), brain-isolated mitochondria were measured for mitochondrial respiration. Brain tissue ATP concentrations, acyl-Coenzyme A thioesters, and mitochondrial content were also measured. RESULTS: The cyanide group showed significantly increased lactate and decreased hypotension with decreased cerebral CIV-linked mitochondrial respiration. There was also a significant decrease in cerebral ATP concentration in the cyanide group and a significantly higher cerebral lactate-to-pyruvate ratio (LPR). In addition, we also found decreased expression of Complex III and IV protein expression in brain tissue from the cyanide group. Finally, there was no change in acyl-coenzyme A thioesters between the two groups. CONCLUSIONS: The key finding demonstrates mitochondrial dysfunction in brain tissue that corresponds with a decrease in mitochondrial function, ATP concentrations, and an elevated LPR indicating brain dysfunction at a sub-lethal dose of cyanide.

Ketogenic Diet for Neonatal Hypoxic-Ischemic Encephalopathy.

The prevalence of neonatal hypoxic-ischemic encephalopathy (HIE), a devastating neurological injury, is increasing; thus, effective treatments and preventions are urgently needed. The underlying pathology of HIE remains unclear; recent research has focused on elucidating key features of the disease. A variety of diseases can be alleviated by consuming a ketogenic diet (KD) despite differences in pathogenesis and features, given the common mechanisms of KD-induced effects. Dietary modification is the most translatable, cost-efficient, and safest approach to treat acute or chronic neurological disorders and reduces reliance on pharmaceutical treatments. Evidence suggests that the KD can exert beneficial effects in animal models and in humans with brain injuries. The efficacy of the KD in preventing neuronal damage, motor alterations, and cognitive decline varies. Moreover, the KD may provide an alternative source of energy, enhance mitochondrial function, and reduce the expression of inflammatory and apoptotic mediators. Thus, this diet has attracted interest as a potential therapy for HIE. This review examined the role of the KD in HIE treatment and described the mechanisms by which ketone bodies (KBs) exert effects under pathological conditions and protect against brain damage; the evidence supports the implementation of dietary interventions as a therapeutic strategy for HIE. Future research should aim to elucidate the underlying mechanisms of the KD in patients with HIE and determine whether the effect of the KD on clinical outcomes can be reproduced in humans.

The effects of acute high-intensity aerobic exercise on cognitive performance: A structured narrative review.

It is well established that acute moderate-intensity exercise improves cognitive performance. However, the effects of acute high-intensity aerobic exercise on cognitive performance have not been well characterized. In this review, we summarize the literature investigating the exercise-cognition interaction, especially focusing on high-intensity aerobic exercise. We discuss methodological and physiological factors that potentially mediate cognitive performance in response to high-intensity exercise. We propose that the effects of high-intensity exercise on cognitive performance are primarily affected by the timing of cognitive task (during vs. after exercise, and the time delay after exercise). In particular, cognitive performance is more likely to be impaired during high-intensity exercise when both cognitive and physiological demands are high and completed simultaneously (i.e., the dual-task paradigm). The effects may also be affected by the type of cognitive task, physical fitness, exercise mode/duration, and age. Second, we suggest that interactions between changes in regional cerebral blood flow (CBF), cerebral oxygenation, cerebral metabolism, neuromodulation by neurotransmitters/neurotrophic factors, and a variety of psychological factors are promising candidates that determine cognitive performance in response to acute high-intensity exercise. The present review has implications for recreational, sporting, and occupational activities where high cognitive and physiological demands are required to be completed concurrently.