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Open AccessArticle

Quantification of the Tissue Oxygenation Delay Induced by Breath-Holding in Patients with Carotid Atherosclerosis

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Andrés Quiroga

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Sergio Novi

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Giovani Martins

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Luis Felipe Bortoletto

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Wagner Avelar

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Ana Terezinha Guillaumon

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Li Min Li

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Fernando Cendes

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Rickson C. Mesquita

Metabolites 2022, 12(11), 1156; https://doi.org/10.3390/metabo12111156 - 21 Nov 2022

Viewed by 822

Abstract

Carotid artery stenosis (CAS) is a common vascular disease with long-term consequences for the brain. Although CAS is strongly associated with impaired cerebral hemodynamics and neurodegeneration, the mechanisms underlying hemodynamic impairment in the microvasculature remain unknown. In this work, we employed functional near-infrared [...] Read more.

Carotid artery stenosis (CAS) is a common vascular disease with long-term consequences for the brain. Although CAS is strongly associated with impaired cerebral hemodynamics and neurodegeneration, the mechanisms underlying hemodynamic impairment in the microvasculature remain unknown. In this work, we employed functional near-infrared spectroscopy (fNIRS) to introduce a methodological approach for quantifying the temporal delay of the evoked hemodynamic response. The method was validated during a vasodilatory task (breath-holding) in 50 CAS patients and 20 controls. Our results suggest that the hemodynamic response to breath-holding can be delayed by up to 6 s in the most severe patients, a significant increase from the median 4 s measured for the control group (p = 0.01). In addition, the fraction of brain regions that responded to the task decreased as the CAS severity increased, from a median of 90% in controls to 73% in the most severe CAS group (p = 0.04). The presence of collateral circulation increases the response to breath-holding and decreases the average time delays across the brain, although the number of communicating arteries alone cannot predict these fNIRS-based hemodynamic variables (p > 0.09). Overall, this work proposes a method to quantitatively assess impaired cerebral hemodynamics in CAS patients. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessArticle

Development of an Endoscopic Auto-Fluorescent Sensing Device to Aid in the Detection of Breast Cancer and Inform Photodynamic Therapy

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Brandon Gaitan

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Collin Inglut

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Udayakumar Kanniyappan

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Metabolites 2022, 12(11), 1097; https://doi.org/10.3390/metabo12111097 - 11 Nov 2022

Viewed by 639

Abstract

Breast cancer is the most diagnosed cancer type in women, with it being the second most deadly cancer in terms of total yearly mortality. Due to the prevalence of this disease, better methods are needed for both detection and treatment. Reduced nicotinamide adenine [...] Read more.

Breast cancer is the most diagnosed cancer type in women, with it being the second most deadly cancer in terms of total yearly mortality. Due to the prevalence of this disease, better methods are needed for both detection and treatment. Reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) are autofluorescent biomarkers that lend insight into cell and tissue metabolism. As such, we developed an endoscopic device to measure these metabolites in tissue to differentiate between malignant tumors and normal tissue. We performed initial validations in liquid phantoms as well as compared to a previously validated redox imaging system. We also imaged ex vivo tissue samples after modulation with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP) and a combination of rotenone and antimycin A. We then imaged the rim and the core of MDA-MB-231 breast cancer tumors, with our results showing that the core of a cancerous lesion has a significantly higher optical redox ratio ([FAD]/([FAD] + [NADH])) than the rim, which agrees with previously published results. The mouse muscle tissues exhibited a significantly lower FAD, higher NADH, and lower redox ratio compared to the tumor core or rim. We also used the endoscope to measure NADH and FAD after photodynamic therapy treatment, a light-activated treatment methodology. Our results found that the NADH signal increases in the malignancy rim and core, while the core of cancers demonstrated a significant increase in the FAD signal. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessArticle

Assessing the Sensitivity of Multi-Distance Hyperspectral NIRS to Changes in the Oxidation State of Cytochrome C Oxidase in the Brain

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Metabolites 2022, 12(9), 817; https://doi.org/10.3390/metabo12090817 - 31 Aug 2022

Viewed by 1009

Abstract

Near-infrared spectroscopy (NIRS) measurements of tissue oxygen saturation (StO₂) are frequently used during vascular and cardiac surgeries as a non-invasive means of assessing brain health; however, signal contamination from extracerebral tissues remains a concern. As an alternative, hyperspectral (hs)NIRS can be [...] Read more.

Near-infrared spectroscopy (NIRS) measurements of tissue oxygen saturation (StO₂) are frequently used during vascular and cardiac surgeries as a non-invasive means of assessing brain health; however, signal contamination from extracerebral tissues remains a concern. As an alternative, hyperspectral (hs)NIRS can be used to measure changes in the oxidation state of cytochrome c oxidase (ΔoxCCO), which provides greater sensitivity to the brain given its higher mitochondrial concentration versus the scalp. The purpose of this study was to evaluate the depth sensitivity of the oxCCO signal to changes occurring in the brain and extracerebral tissue components. The oxCCO assessment was conducted using multi-distance hsNIRS (source-detector separations = 1 and 3 cm), and metabolic changes were compared to changes in StO₂. Ten participants were monitored using an in-house system combining hsNIRS and diffuse correlation spectroscopy (DCS). Data were acquired during carotid compression (CC) to reduce blood flow and hypercapnia to increase flow. Reducing blood flow by CC resulted in a significant decrease in oxCCO measured at r_SD = 3 cm but not at 1 cm. In contrast, significant changes in StO₂ were found at both distances. Hypercapnia caused significant increases in StO₂ and oxCCO at r_SD = 3 cm, but not at 1 cm. Extracerebral contamination resulted in elevated StO₂ but not oxCCO after hypercapnia, which was significantly reduced by applying regression analysis. This study demonstrated that oxCCO was less sensitive to extracerebral signals than StO₂. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessArticle

Optical Redox Imaging of Ex Vivo Hippocampal Tissue Reveals Age-Dependent Alterations in the 5XFAD Mouse Model of Alzheimer’s Disease

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Metabolites 2022, 12(9), 786; https://doi.org/10.3390/metabo12090786 - 25 Aug 2022

Viewed by 776

Abstract

A substantial decline in nicotinamide adenine dinucleotide (NAD) has been reported in brain tissue homogenates or neurons isolated from Alzheimer’s disease (AD) models. NAD, together with flavin adenine dinucleotide (FAD), critically supports energy metabolism and maintains mitochondrial redox homeostasis. Optical redox imaging (ORI) [...] Read more.

A substantial decline in nicotinamide adenine dinucleotide (NAD) has been reported in brain tissue homogenates or neurons isolated from Alzheimer’s disease (AD) models. NAD, together with flavin adenine dinucleotide (FAD), critically supports energy metabolism and maintains mitochondrial redox homeostasis. Optical redox imaging (ORI) of the intrinsic fluorescence of reduced NAD (NADH) and oxidized FAD yields cellular redox and metabolic information and provides biomarkers for a variety of pathological conditions. However, its utility in AD has not been characterized at the tissue level. We performed ex vivo ORI of freshly dissected hippocampi from a well-characterized AD mouse model with five familial Alzheimer’s disease mutations (5XFAD) and wild type (WT) control littermates at various ages. We found (1) a significant increase in the redox ratio with age in the hippocampi of both the WT control and the 5XFAD model, with a more prominent redox shift in the AD hippocampi; (2) a higher NADH in the 5XFAD versus WT hippocampi at the pre-symptomatic age of 2 months; and (3) a negative correlation between NADH and Aβ₄₂ level, a positive correlation between Fp and Aβ₄₂ level, and a positive correlation between redox ratio and Aβ₄₂ level in the AD hippocampi. These findings suggest that the ORI can be further optimized to conveniently study the metabolism of freshly dissected brain tissues in animal models and identify early AD biomarkers. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessArticle

Correlation of Cerebral Microdialysis with Non-Invasive Diffuse Optical Cerebral Hemodynamic Monitoring during Deep Hypothermic Cardiopulmonary Bypass

Metabolites 2022, 12(8), 737; https://doi.org/10.3390/metabo12080737 - 10 Aug 2022

Viewed by 994

Abstract

Neonates undergoing cardiac surgery involving aortic arch reconstruction are at an increased risk for hypoxic-ischemic brain injury. Deep hypothermia is utilized to help mitigate this risk when periods of circulatory arrest are needed for surgical repair. Here, we investigate correlations between non-invasive optical [...] Read more.

Neonates undergoing cardiac surgery involving aortic arch reconstruction are at an increased risk for hypoxic-ischemic brain injury. Deep hypothermia is utilized to help mitigate this risk when periods of circulatory arrest are needed for surgical repair. Here, we investigate correlations between non-invasive optical neuromonitoring of cerebral hemodynamics, which has recently shown promise for the prediction of postoperative white matter injury in this patient population, and invasive cerebral microdialysis biomarkers. We compared cerebral tissue oxygen saturation (StO₂), relative total hemoglobin concentration (rTHC), and relative cerebral blood flow (rCBF) measured by optics against the microdialysis biomarkers of metabolic stress and injury (lactate–pyruvate ratio (LPR) and glycerol) in neonatal swine models of deep hypothermic cardiopulmonary bypass (DHCPB), selective antegrade cerebral perfusion (SACP), and deep hypothermic circulatory arrest (DHCA). All three optical parameters were negatively correlated with LPR and glycerol in DHCA animals. Elevation of LPR was found to precede the elevation of glycerol by 30–60 min. From these data, thresholds for the detection of hypoxic-ischemia-associated cerebral metabolic distress and neurological injury are suggested. In total, this work provides insight into the timing and mechanisms of neurological injury following hypoxic-ischemia and reports a quantitative relationship between hypoxic-ischemia severity and neurological injury that may inform DHCA management. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessArticle

Non-Invasive Spectroscopy for Measuring Cerebral Tissue Oxygenation and Metabolism as a Function of Cerebral Perfusion Pressure

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Jana M. Kainerstorfer

Metabolites 2022, 12(7), 667; https://doi.org/10.3390/metabo12070667 - 20 Jul 2022

Viewed by 849

Abstract

Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) measure cerebral hemodynamics, which in turn can be used to assess the cerebral metabolic rate of oxygen (CMRO₂) and cerebral autoregulation (CA). However, current mathematical models for CMRO₂ estimation make assumptions that [...] Read more.

Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) measure cerebral hemodynamics, which in turn can be used to assess the cerebral metabolic rate of oxygen (CMRO₂) and cerebral autoregulation (CA). However, current mathematical models for CMRO₂ estimation make assumptions that break down for cerebral perfusion pressure (CPP)-induced changes in CA. Here, we performed preclinical experiments with controlled changes in CPP while simultaneously measuring NIRS and DCS at rest. We observed changes in arterial oxygen saturation (~10%) and arterial blood volume (~50%) with CPP, two variables often assumed to be constant in CMRO₂ estimations. Hence, we propose a general mathematical model that accounts for these variations when estimating CMRO₂ and validate its use for CA monitoring on our experimental data. We observed significant changes in the various oxygenation parameters, including the coupling ratio (CMRO₂/blood flow) between regions of autoregulation and dysregulation. Our work provides an appropriate model and preliminary experimental evidence for the use of NIRS- and DCS-based tissue oxygenation and metabolism metrics for non-invasive diagnosis of CA health in CPP-altering neuropathologies. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessArticle

Broadband-NIRS System Identifies Epileptic Focus in a Child with Focal Cortical Dysplasia—A Case Study

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Aikaterini Vezyroglou

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Metabolites 2022, 12(3), 260; https://doi.org/10.3390/metabo12030260 - 17 Mar 2022

Cited by 2 | Viewed by 1451

Abstract

Epileptic seizures are transiently occurring symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Previous functional near-infrared spectroscopy (fNIRS) studies during seizures have focused in only monitoring the brain oxygenation and haemodynamic changes. However, few tools are available to measure [...] Read more.

Epileptic seizures are transiently occurring symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Previous functional near-infrared spectroscopy (fNIRS) studies during seizures have focused in only monitoring the brain oxygenation and haemodynamic changes. However, few tools are available to measure actual cellular metabolism during seizures, especially at the bedside. Here we use an in-house developed multichannel broadband NIRS (or bNIRS) system, that, alongside the changes in oxy-, deoxy- haemoglobin concentration (HbO₂, HHb), also quantifies the changes in oxidised cytochrome-c-oxidase Δ(oxCCO), a marker of cellular oxygen metabolism, simultaneously over 16 different brain locations. We used bNIRS to measure metabolic activity alongside brain tissue haemodynamics/oxygenation during 17 epileptic seizures at the bedside of a 3-year-old girl with seizures due to an extensive malformation of cortical development in the left posterior quadrant. Simultaneously Video-EEG data was recorded from 12 channels. Whilst we did observe the expected increase in brain tissue oxygenation (HbD) during seizures, it was almost diminished in the area of the focal cortical dysplasia. Furthermore, in the area of seizure origination (epileptic focus) ΔoxCCO decreased significantly at the time of seizure generalization when compared to the mean change in all other channels. We hypothesize that this indicates an incapacity to sustain and increase brain tissue metabolism during seizures in the region of the epileptic focus. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessArticle

Photobiomodulation at Different Wavelengths Boosts Mitochondrial Redox Metabolism and Hemoglobin Oxygenation: Lasers vs. Light-Emitting Diodes In Vivo

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Metabolites 2022, 12(2), 103; https://doi.org/10.3390/metabo12020103 - 23 Jan 2022

Cited by 7 | Viewed by 2865

Abstract

Our group previously examined 8 min photobiomodulation (PBM) by 1064 nm laser on the human forearm in vivo to determine its significant effects on vascular hemodynamics and cytochrome c oxidase redox activity. Since PBM uses a wide array of wavelengths, in this paper, [...] Read more.

Our group previously examined 8 min photobiomodulation (PBM) by 1064 nm laser on the human forearm in vivo to determine its significant effects on vascular hemodynamics and cytochrome c oxidase redox activity. Since PBM uses a wide array of wavelengths, in this paper, we investigated (i) whether different wavelengths of lasers induced different PBM effects, and (ii) if a light-emitting diode (LED) at a similar wavelength to a laser could induce similar PBM effects. A broadband near-infrared spectroscopy (bbNIRS) system was utilized to assess concentration changes in oxygenated hemoglobin (Δ[HbO]) and oxidized cytochrome c oxidase (Δ[oxCCO]) during and after PBM with lasers at 800 nm, 850 nm, and 1064 nm, as well as a LED at 810 nm. Two groups of 10 healthy participants were measured before, during, and after active and sham PBM on their forearms. All results were tested for significance using repeated measures ANOVA. Our results showed that (i) lasers at all three wavelengths enabled significant increases in Δ[HbO] and Δ[oxCCO] of the human forearm while the 1064 nm laser sustained the increases longer, and that (ii) the 810-nm LED with a moderate irradiance (≈135 mW/cm²) induced measurable and significant rises in Δ[HbO] and Δ[oxCCO] with respect to the sham stimulation on the human forearm. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessArticle

Metabolic Connectivity and Hemodynamic-Metabolic Coherence of Human Prefrontal Cortex at Rest and Post Photobiomodulation Assessed by Dual-Channel Broadband NIRS

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Nghi Cong Dung Truong

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Hanli Liu

Metabolites 2022, 12(1), 42; https://doi.org/10.3390/metabo12010042 - 05 Jan 2022

Cited by 5 | Viewed by 1099

Abstract

Billions of neurons in the human brain form neural networks with oscillation rhythms. Infra-slow oscillation (ISO) presents three main physiological sources: endogenic, neurogenic, and myogenic vasomotions. Having an in vivo methodology for the absolute quantification of ISO from the human brain can facilitate [...] Read more.

Billions of neurons in the human brain form neural networks with oscillation rhythms. Infra-slow oscillation (ISO) presents three main physiological sources: endogenic, neurogenic, and myogenic vasomotions. Having an in vivo methodology for the absolute quantification of ISO from the human brain can facilitate the detection of brain abnormalities in cerebral hemodynamic and metabolic activities. In this study, we introduced a novel measurement-plus-analysis framework for the non-invasive quantification of prefrontal ISO by (1) taking dual-channel broadband near infrared spectroscopy (bbNIRS) measurements from 12 healthy humans during a 6-min rest and 4-min post transcranial photobiomodulation (tPBM) and (2) performing wavelet transform coherence (WTC) analysis on the measured time series data. The WTC indexes (IC, between 0 and 1) enabled the assessment of ipsilateral hemodynamic-metabolic coherence and bilateral functional connectivity in each ISO band of the human prefrontal cortex. At rest, bilateral hemodynamic connectivity was consistent across the three ISO bands (IC ≅ 0.66), while bilateral metabolic connectivity was relatively weaker. For post-tPBM/sham comparison, our analyses revealed three key findings: 8-min, right-forehead, 1064-nm tPBM (1) enhanced the amplitude of metabolic oscillation bilaterally, (2) promoted the bilateral metabolic connectivity of neurogenic rhythm, and (3) made the main effect on endothelial cells, causing alteration of hemodynamic-metabolic coherence on each side of the prefrontal cortex. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessArticle

Exercise Training Increases Resting Calf Muscle Oxygen Metabolism in Patients with Peripheral Artery Disease

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Metabolites 2021, 11(12), 814; https://doi.org/10.3390/metabo11120814 - 29 Nov 2021

Cited by 3 | Viewed by 1598

Abstract

Exercise training can mitigate symptoms of claudication (walking-induced muscle pain) in patients with peripheral artery disease (PAD). One adaptive response enabling this improvement is enhanced muscle oxygen metabolism. To explore this issue, we used arterial-occlusion diffuse optical spectroscopy (AO-DOS) to measure the effects [...] Read more.

Exercise training can mitigate symptoms of claudication (walking-induced muscle pain) in patients with peripheral artery disease (PAD). One adaptive response enabling this improvement is enhanced muscle oxygen metabolism. To explore this issue, we used arterial-occlusion diffuse optical spectroscopy (AO-DOS) to measure the effects of exercise training on the metabolic rate of oxygen (MRO₂) in resting calf muscle. Additionally, venous-occlusion DOS (VO-DOS) and frequency-domain DOS (FD-DOS) were used to measure muscle blood flow (F) and tissue oxygen saturation (StO₂), and resting calf muscle oxygen extraction fraction (OEF) was calculated from MRO₂, F, and blood hemoglobin. Lastly, the venous/arterial ratio (γ) of blood monitored by FD-DOS was calculated from OEF and StO₂. PAD patients who experience claudication (n = 28) were randomly assigned to exercise and control groups. Patients in the exercise group received 3 months of supervised exercise training. Optical measurements were obtained at baseline and at 3 months in both groups. Resting MRO₂, OEF, and F, respectively, increased by 30% (12%, 44%) (p < 0.001), 17% (6%, 45%) (p = 0.003), and 7% (0%, 16%) (p = 0.11), after exercise training (median (interquartile range)). The pre-exercise γ was 0.76 (0.61, 0.89); it decreased by 12% (35%, 6%) after exercise training (p = 0.011). Improvement in exercise performance was associated with a correlative increase in resting OEF (R = 0.45, p = 0.02). Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessArticle

Diffuse Optical Spectroscopy Assessment of Resting Oxygen Metabolism in the Leg Musculature

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Metabolites 2021, 11(8), 496; https://doi.org/10.3390/metabo11080496 - 29 Jul 2021

Cited by 3 | Viewed by 1529

Abstract

We lack reliable methods to continuously assess localized, resting-state muscle activity that are comparable across individuals. Near-infrared spectroscopy (NIRS) provides a low-cost, non-invasive means to assess localized, resting-state muscle oxygen metabolism during venous or arterial occlusions (VO_2VO and VO_2AO, respectively). [...] Read more.

We lack reliable methods to continuously assess localized, resting-state muscle activity that are comparable across individuals. Near-infrared spectroscopy (NIRS) provides a low-cost, non-invasive means to assess localized, resting-state muscle oxygen metabolism during venous or arterial occlusions (VO_2VO and VO_2AO, respectively). However, this technique is not suitable for continuous monitoring, and its utility is limited to those who can tolerate occlusions. Combining NIRS with diffuse correlated spectroscopy (DCS) enables continuous measurement of an index of muscle oxygen metabolism (VO_2i). Despite the lack of previous validation, VO_2i is employed as a measure of oxygen metabolism in the muscle. Here we characterized measurement repeatability and compared VO_2i with VO_2VO and VO_2AO in the medial gastrocnemius (MG) in 9 healthy adults. Intra-participant repeatability of VO_2i, VO_2VO, and VO_2AO were excellent. VO_2i was not significantly correlated with VO_2AO (p = 0.15) nor VO_2VO (p = 0.55). This lack of correlation suggests that the variability in the calibration coefficient between VO_2i and VO_2AO/VO_2VO in the MG is substantial across participants. Thus, it is preferable to calibrate VO_2i prior to every monitoring session. Important future work is needed to compare VO_2i against gold standard modalities such as positron emission tomography or magnetic resonance imaging. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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Open AccessStudy Protocol

Improving Infant Hydrocephalus Outcomes in Uganda: A Longitudinal Prospective Study Protocol for Predicting Developmental Outcomes and Identifying Patients at Risk for Early Treatment Failure after ETV/CPC

Metabolites 2022, 12(1), 78; https://doi.org/10.3390/metabo12010078 - 14 Jan 2022

Cited by 2 | Viewed by 1660

Abstract

Infant hydrocephalus poses a severe global health burden; 80% of cases occur in the developing world where patients have limited access to neurosurgical care. Surgical treatment combining endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC), first practiced at CURE Children’s Hospital of Uganda [...] Read more.

Infant hydrocephalus poses a severe global health burden; 80% of cases occur in the developing world where patients have limited access to neurosurgical care. Surgical treatment combining endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC), first practiced at CURE Children’s Hospital of Uganda (CCHU), is as effective as standard ventriculoperitoneal shunt (VPS) placement while requiring fewer resources and less post-operative care. Although treatment focuses on controlling ventricle size, this has little association with treatment failure or long-term outcome. This study aims to monitor the progression of hydrocephalus and treatment response, and investigate the association between cerebral physiology, brain growth, and neurodevelopmental outcomes following surgery. We will enroll 300 infants admitted to CCHU for treatment. All patients will receive pre/post-operative measurements of cerebral tissue oxygenation (SO₂), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO₂) using frequency-domain near-infrared combined with diffuse correlation spectroscopies (FDNIRS-DCS). Infants will also receive brain imaging, to monitor tissue/ventricle volume, and neurodevelopmental assessments until two years of age. This study will provide a foundation for implementing cerebral physiological monitoring to establish evidence-based guidelines for hydrocephalus treatment. This paper outlines the protocol, clinical workflow, data management, and analysis plan of this international, multi-center trial. Full article

(This article belongs to the Special Issue Optical Assessment of Metabolism)

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