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# Quantification of the severity of hypoxic-ischemic brain injury in a neonatal preclinical model using measurements of cytochrome-c-oxidase from a miniature broadband-near-infrared spectroscopy system

Neurophotonics

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### Abstract.

We describe the development of a miniaturized broadband near-infrared spectroscopy system (bNIRS), which measures changes in cerebral tissue oxyhemoglobin ( $[ HbO 2 ]$ ) and deoxyhemoglobin ([HHb]) plus tissue metabolism via changes in the oxidation state of cytochrome-c-oxidase ([oxCCO]). The system is based on a small light source and a customized mini-spectrometer. We assessed the instrument in a preclinical study in 27 newborn piglets undergoing transient cerebral hypoxia-ischemia (HI). We aimed to quantify the recovery of the HI insult and estimate the severity of the injury. The recovery in brain oxygenation ( $Δ [ HbDiff ] = Δ [ HbO 2 ] − Δ [ HHb ]$ ), blood volume ( $Δ [ HbT ] = Δ [ HbO 2 ] + Δ [ HHb ]$ ), and metabolism ( $Δ [ oxCCO ]$ ) for up to 30 min after the end of HI were quantified in percentages using the recovery fraction (RF) algorithm, which quantifies the recovery of a signal with respect to baseline. The receiver operating characteristic analysis was performed on bNIRS-RF measurements compared to proton ( $H 1$ ) magnetic resonance spectroscopic (MRS)-derived thalamic lactate/N-acetylaspartate (Lac/NAA) measured at 24-h post HI insult; Lac/NAA peak area ratio is an accurate surrogate marker of neurodevelopmental outcome in babies with neonatal HI encephalopathy. The $Δ [ oxCCO ]$ -RF cut-off threshold of 79% within 30 min of HI predicted injury severity based on Lac/NAA with high sensitivity (100%) and specificity (93%). A significant difference in thalamic Lac/NAA was noticed ( $p < 0.0001$ ) between the two groups based on this cut-off threshold of 79% $Δ [ oxCCO ]$ -RF. The severe injury group ( $n = 13$ ) had $∼ 30 %$ smaller recovery in $Δ [ HbDiff ]$ -RF ( $p = 0.0001$ ) and no significant difference was observed in $Δ [ HbT ]$ -RF between groups. At 48 h post HI, significantly higher $P 31$ -MRS-measured inorganic phosphate/exchangeable phosphate pool (epp) ( $p = 0.01$ ) and reduced phosphocreatine/epp ( $p = 0.003$ ) were observed in the severe injury group indicating persistent cerebral energy depletion. Based on these results, the bNIRS measurement of the oxCCO recovery fraction offers a noninvasive real-time biomarker of brain injury severity within 30 min following HI insult.

### Most cited references54

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### Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters.

(1977)
The relatively good transparency of biological materials in the near infrared region of the spectrum permits sufficient photon transmission through organs in situ for the monitoring of cellular events. Observations by infrared transillumination in the exposed heart and in the brain in cephalo without surgical intervention show that oxygen sufficiency for cytochrome a,a3, function, changes in tissue blood volume, and the average hemoglobin-oxyhemoglobin equilibrium can be recorded effectively and in continuous fashion for research and clinical purposes. The copper atom associated with heme a3 did not respond to anoxia and may be reduced under normoxic conditions, whereas the heme-a copper was at least partially reducible.
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### Sensitivity, specificity, receiver-operating characteristic (ROC) curves and likelihood ratios: communicating the performance of diagnostic tests.

(2008)
* Diagnostic accuracy studies address how well a test identifies the target condition of interest. * Sensitivity, specificity, predictive values and likelihood ratios (LRs) are all different ways of expressing test performance. * Receiver operating characteristic (ROC) curves compare sensitivity versus specificity across a range of values for the ability to predict a dichotomous outcome. Area under the ROC curve is another measure of test performance. * All of these parameters are not intrinsic to the test and are determined by the clinical context in which the test is employed. * High sensitivity corresponds to high negative predictive value and is the ideal property of a "rule-out" test. * High specificity corresponds to high positive predictive value and is the ideal property of a "rule-in" test. * LRs leverage pre-test into post-test probabilities of a condition of interest and there is some evidence that they are more intelligible to users.
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### Simulation of Near-Infrared Light Absorption Considering Individual Head and Prefrontal Cortex Anatomy: Implications for Optical Neuroimaging

(2011)
Functional near-infrared spectroscopy (fNIRS) is an established optical neuroimaging method for measuring functional hemodynamic responses to infer neural activation. However, the impact of individual anatomy on the sensitivity of fNIRS measuring hemodynamics within cortical gray matter is still unknown. By means of Monte Carlo simulations and structural MRI of 23 healthy subjects (mean age: years), we characterized the individual distribution of tissue-specific NIR-light absorption underneath 24 prefrontal fNIRS channels. We, thereby, investigated the impact of scalp-cortex distance (SCD), frontal sinus volume as well as sulcal morphology on gray matter volumes ( ) traversed by NIR-light, i.e. anatomy-dependent fNIRS sensitivity. The NIR-light absorption between optodes was distributed describing a rotational ellipsoid with a mean penetration depth of considering the deepest of light. Of the detected photon packages scalp and bone absorbed and absorbed of the energy. The mean volume was negatively correlated ( ) with the SCD and frontal sinus volume ( ) and was reduced by in subjects with relatively large compared to small frontal sinus. Head circumference was significantly positively correlated with the mean SCD ( ) and the traversed frontal sinus volume ( ). Sulcal morphology had no significant impact on . Our findings suggest to consider individual SCD and frontal sinus volume as anatomical factors impacting fNIRS sensitivity. Head circumference may represent a practical measure to partly control for these sources of error variance.
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### Author and article information

###### Journal
Neurophotonics
Neurophotonics
NEUROW
NPh
Neurophotonics
Society of Photo-Optical Instrumentation Engineers
2329-423X
2329-4248
14 November 2019
October 2019
: 6
: 4
###### Affiliations
[a ]University College London , Department of Medical Physics and Biomedical Engineering, London, United Kingdom
[b ]University College London , Institute for Women’s Health, London, United Kingdom
[c ]University College London Hospital , Department of Medical Physics and Biomedical Engineering, London, United Kingdom
###### Author notes
[* ]Address all correspondence to Ilias Tachtsidis, E-mail: i.tachtsidis@ 123456ucl.ac.uk
###### Article
NPh-19069R 19069R
10.1117/1.NPh.6.4.045009
6855218
31737744
© The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
###### Page count
Figures: 8, Tables: 5, References: 71, Pages: 17
###### Funding
Funded by: Wellcome Trust https://doi.org/10.13039/100004440
Award ID: 104580/Z/14/Z
Funded by: UK Department of Health’s NIHR BRC
###### Categories
Research Papers
Paper