Nimodipine Protects Vascular and Cognitive Function in an Animal Model of Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease is a common cause of vascular cognitive impairment and dementia. There is an urgent need for preventative treatments for vascular cognitive impairment and dementia, and reducing vascular dysfunction may provide a therapeutic route. Here, we investigate whether the chronic administration of nimodipine, a central nervous system-selective dihydropyridine calcium channel blocking agent, protects vascular, metabolic, and cognitive function in an animal model of cerebral small vessel disease, the spontaneously hypertensive stroke-prone rat. METHODS: Male spontaneously hypertensive stroke-prone rats were randomly allocated to receive either a placebo (n=24) or nimodipine (n=24) diet between 3 and 6 months of age. Animals were examined daily for any neurological deficits, and vascular function was assessed in terms of neurovascular and neurometabolic coupling at 3 and 6 months of age, and cerebrovascular reactivity at 6 months of age. Cognitive function was evaluated using the novel object recognition test at 6 months of age. RESULTS: Six untreated control animals were terminated prematurely due to strokes, including one due to seizure, but no treated animals experienced strokes and so had a higher survival (P=0.0088). Vascular function was significantly impaired with disease progression, but nimodipine treatment partially preserved neurovascular coupling and neurometabolic coupling, indicated by larger (P<0.001) and more prompt responses (P<0.01), and less habituation upon repeated stimulation (P<0.01). Also, animals treated with nimodipine showed greater cerebrovascular reactivity, indicated by larger dilation of arterioles (P=0.015) and an increase in blood flow velocity (P=0.001). This protection of vascular and metabolic function achieved by nimodipine treatment was associated with better cognitive function (P<0.001) in the treated animals. CONCLUSIONS: Chronic treatment with nimodipine protects from strokes, and vascular and cognitive deficits in spontaneously hypertensive stroke-prone rat. Nimodipine may provide an effective preventive treatment for stroke and cognitive decline in cerebral small vessel disease.

Early assessment of injury with optical markers in a piglet model of neonatal encephalopathy.

BACKGROUND: Opportunities for adjunct therapies with cooling in neonatal encephalopathy are imminent; however, robust biomarkers of early assessment are lacking. Using an optical platform of broadband near-infrared spectroscopy and diffuse correlation spectroscopy to directly measure mitochondrial metabolism (oxCCO), oxygenation (HbD), cerebral blood flow (CBF), we hypothesised optical indices early (1-h post insult) after hypoxia-ischaemia (HI) predicts insult severity and outcome. METHODS: Nineteen newborn large white piglets underwent continuous neuromonitoring as controls or following moderate or severe HI. Optical indices were expressed as mean semblance (phase difference) and coherence (spectral similarity) between signals using wavelet analysis. Outcome markers included the lactate/N-acetyl aspartate (Lac/NAA) ratio at 6 h on proton MRS and TUNEL cell count. RESULTS: CBF-HbD semblance (cerebrovascular dysfunction) correlated with BGT and white matter (WM) Lac/NAA (r2 = 0.46, p = 0.004, r2 = 0.45, p = 0.004, respectively), TUNEL cell count (r2 = 0.34, p = 0.02) and predicted both initial insult (r2 = 0.62, p = 0.002) and outcome group (r2 = 0.65 p = 0.003). oxCCO-HbD semblance (cerebral metabolic dysfunction) correlated with BGT and WM Lac/NAA (r2 = 0.34, p = 0.01 and r2 = 0.46, p = 0.002, respectively) and differentiated between outcome groups (r2 = 0.43, p = 0.01). CONCLUSION: Optical markers of both cerebral metabolic and vascular dysfunction 1 h after HI predicted injury severity and subsequent outcome in a pre-clinical model. IMPACT: This study highlights the possibility of using non-invasive optical biomarkers for early assessment of injury severity following neonatal encephalopathy, relating to the outcome. Continuous cot-side monitoring of these optical markers can be useful for disease stratification in the clinical population and for identifying infants who might benefit from future adjunct neuroprotective therapies beyond cooling.

Does global change increase the risk of maladaptation of Atlantic salmon migration through joint modifications of river temperature and discharge?

In freshwater ecosystems, water temperature and discharge are two intrinsically associated triggers of key events in the life cycle of aquatic organisms such as the migration of diadromous fishes. However, global changes have already profoundly altered the thermal and hydrological regimes of rivers, affecting the timing of fish migration as well as the environmental conditions under which it occurs. In this study, we focused on Atlantic salmon (Salmo salar), an iconic diadromous species whose individuals migrate between marine nursery areas and continental spawning grounds. An innovative multivariate method was developed to analyse long-term datasets of daily water temperature, discharge and both salmon juvenile downstream and adult upstream migrations in three French rivers (the Bresle, Oir and Nivelle rivers). While all three rivers have gradually warmed over the last 35 years, changes in discharge have been very heterogeneous. Juveniles more frequently used warmer temperatures to migrate. Adults migrating a few weeks before spawning more frequently used warm temperatures associated with high discharges. This has already led to modifications in preferential niches of both life stages and suggests a potential mismatch between these populations' ecological preference and changes in their local environment due to global change.

A hyperspectral imaging system for mapping haemoglobin and cytochrome-c-oxidase concentration changes in the exposed cerebral cortex.

We present a novel hyperspectral imaging (HSI) system using visible and near-infrared (NIR) light on the exposed cerebral cortex of animals, to monitor and quantify in vivo changes in the oxygenation of haemoglobin and in cellular metabolism via measurement of the redox states of cytochrome-c-oxidase (CCO). The system, named hNIR, is based on spectral scanning illumination at 11 bands (600, 630, 665, 784, 800, 818, 835, 851, 868, 881 and 894 nm), using a supercontinuum laser coupled with a rotating Pellin-Broca prism. Image reconstruction is performed with the aid of a Monte Carlo framework for photon pathlength estimation and post-processing correction of partial volume effects. The system is validated on liquid optical phantoms mimicking brain tissue haemodynamics and metabolism, and finally applied in vivo on the exposed cortex of mice undergoing alternating oxygenation challenges. The results of the study demonstrate the capacity of hNIR to map and quantify the haemodynamic and metabolic states of the exposed cortex at microvascular levels. This represents (to the best of our knowledge) the first example of simultaneous mapping and quantification of cerebral haemoglobin and CCO in vivo using visible and NIR HSI, which can potentially become a powerful tool for better understanding brain physiology.

Sexual maturity increases mobility and heterogeneity in individual space use in Atlantic salmon (Salmo salar) parr.

We assessed the effects of sexual maturity on space use in Atlantic salmon (Salmo salar) parr as facultative early maturation enables us to work on individuals belonging to the same cohort. We monitored the space use of 40 1-year-old males in natura throughout a breeding season. First, mature individuals covered longer distances (absolute and upstream) and located within broader home ranges than immature parr. Second, sexual maturity also generated a higher interindividual variability in space use. Finally, mature individuals exhibited a higher probability of association with likely breeding sites on average. However, some mature individuals experienced a lower probability than immature individuals, suggesting that the space use of some mature individuals may not be optimal. Moreover, mature parr exploiting a broader home range or covering longer upstream distances had a higher probability of association with likely breeding sites. Covering longer upstream distances may therefore increase the reproductive success of mature parr, while involving higher energetic costs and a greater risk of predation.

MAESTROS: A Multiwavelength Time-Domain NIRS System to Monitor Changes in Oxygenation and Oxidation State of Cytochrome-C-Oxidase.

We present a multiwavelength, multichannel, time-domain near-infrared spectroscopy system named MAESTROS. This instrument can measure absorption and scattering coefficients and can quantify the concentrations of oxy- and deoxy-haemoglobin ([HbO2], [HHb]), and oxidation state of cytochrome-c-oxidase ([oxCCO]). This system is composed of a supercontinuum laser source coupled with two acousto-optic tuneable filters. The light is collected by four photomultipliers tubes, connected to a router to redirect the signal to a single time-correlated single-photon counting card. The interface between the system and the tissue is based on optical fibres. This arrangement allows us to resolve up to 16 wavelengths, within the range of 650-900 nm, at a sampling rate compatible with the physiology (from 0.5 to 2 Hz). In this paper, we describe the system and assess its performance based on two specifically designed protocols for photon migration instruments, the basic instrument protocol and nEUROPt protocols, and on a well characterized liquid phantom based on Intralipid and water. Then, the ability to resolve [HbO2 ], [HHb], and [oxCCO] is demonstrated on a homogeneous liquid phantom, based on blood for [HbO2], [HHb], and yeast for [oxCCO]. In the future, the system could be used to monitor brain tissue physiology.

Broadband time-resolved multi-channel functional near-infrared spectroscopy system to monitor in vivo physiological changes of human brain activity.

We have developed a broadband time-resolved multi-channel near-infrared spectroscopy system that can monitor the physiological responses of the adult human brain. This system is composed of a supercontinuum laser for the source part and of an intensified charge-coupled device camera coupled with an imaging spectrometer for the detection part. It allows the detection of the spectral, from 600 to 900 nm, and spatial dimensions as well as the arrival time of photon information simultaneously. We describe the setup and its characterization in terms of temporal instrument response function, wavelength sensitivity, and stability. The ability of the system to detect the hemodynamic response is then demonstrated. First, an in vivo experiment on an adult volunteer was performed to monitor the response in the arm during a cuff occlusion. Second, the response in the brain during a cognitive task was monitored on a group of five healthy volunteers. Moreover, looking at the response at different time windows, we could monitor the hemodynamic response in depth, enhancing the detection of the cortical activation. Those first results demonstrate the ability of our system to discriminate between the responses of superficial and deep tissues, addressing an important issue in functional near-infrared spectroscopy.

Hyperspectral Imaging of the Hemodynamic and Metabolic States of the Exposed Cortex: Investigating a Commercial Snapshot Solution.

Hyperspectral imaging (HSI) systems have the potential to retrieve in vivo hemodynamic and metabolic signals from the exposed cerebral cortex. The use of multiple narrow wavelength bands in the near infrared (NIR) range theoretically allows not only to image brain tissue oxygenation and hemodynamics via mapping of hemoglobin concentration changes, but also to directly quantify cerebral metabolism via measurement of the redox states of mitochondrial cytochrome-c-oxidase (CCO). The aim of this study is to assess the possibility of performing hyperspectral imaging of in vivo cerebral oxyhemoglobin (HbO2), deoxyhemoglobin (HHb) and oxidized CCO (oxCCO) using commercially available HSI devices. For this reason, a hyperspectral snapshot solution based on Cubert GmbH technology (S185 FireflEYE camera) has been tested on the exposed cortex of mice during normoxic, hypoxic and hyperoxic conditions. The system allows simultaneous acquisition of 138 wavelength bands between 450 and 998 nm, with spectral sampling and resolution of ~4 to 8 nm. From the hyperspectral data, relative changes in concentration of hemoglobin and oxCCO are estimated and hemodynamic and metabolic maps of the imaged cortex are calculated for two different NIR spectral ranges. Spectroscopic analysis at particular regions of interest is also performed, showing typical oxygen-dependent hemodynamic responses. The results highlight some of the potentials of the technology, but also the limitations of the tested commercial solution for such specific application, in particular regarding spatial resolution.

Evaluation of Haemoglobin and Cytochrome Responses During Forearm Ischaemia Using Multi-wavelength Time Domain NIRS.

We demonstrate the ability of a 16-wavelength time domain near-infrared spectroscopy system to monitor changes in oxy- and deoxy haemoglobin ([HbO2] [HHb]) and the oxidation of cytochrome-c-oxidase ([oxCCO]), during forearm ischaemia. We tested two methods to retrieve the concentration changes. The first uses the measured changes in light attenuation and the modified Beer-Lambert law, and the second uses the absorption and scattering estimated by the measured time-point spread function. The system is able to retrieve the concentration changes with both methods, giving similar results. At the end of forearm ischaemia (t = 5 min), we measured an increase in [HHb] of 16.77 ± 2.52 and 16.37 ± 2.33 µMol, and a decrease in [HbO2] of -6.12 ± 1.62 and -5.57 ± 2.02 µMol for method 1 and 2, respectively. At that same time, the changes in [oxCCO] were -0.36 ± 0.33 and -1.40 ± 1.20 µMol, for method 1 and 2, respectively. These small changes in [oxCCO], despite a huge change in haemoglobin, demonstrate the absence of crosstalk and are comparable to previous measurements using broadband NIRS.

Sexual selection leads to a tenfold difference in reproductive success of alternative reproductive tactics in male Atlantic salmon.

The precocious maturation of some male Atlantic salmon (Salmo salar L.) has become a textbook example of alternative mating tactics, but the only estimates of reproductive success available so far are either the collective contribution of precocious males to reproduction in the wild or individual reproductive success in oversimplified experimental conditions. Using genetic parentage analysis on anadromous and precocious potential spawners and their offspring, we quantified components of individual reproductive success of both tactics in a natural population. On average, precocious males produced 2.24 (variance 67.62) offspring, against 27.17 (3080) for anadromous males. For both tactics, most of the variance in reproductive success was due to mating success, with 83% of precocious males having no mate, against 50% for anadromous males. Body size increased reproductive success of anadromous males and tended to decrease precocious males' reproductive success. Although these results do not solve the coexistence of alternative reproductive tactics (ARTs) in Atlantic salmon, their inclusion in comprehensive models of lifetime reproductive success should shed light on the evolution of precocious maturation in Atlantic salmon and its effect on the selection of phenotypic traits.

Investigating cortical hypoxia in multiple sclerosis via time-domain near-infrared spectroscopy.

OBJECTIVES: Hypoperfusion and tissue hypoxia have been implicated as contributory mechanisms in the neuropathology of multiple sclerosis (MS). Our objective has been to study cortical oxygenation in vivo in patients with MS and age-matched controls. METHODS: A custom, multiwavelength time-domain near-infrared spectroscopy system was developed for assessing tissue hypoxia from the prefrontal cortex. A cross-sectional case-control study was undertaken assessing patients with secondary progressive MS (SPMS) and age-matched controls. Co-registered magnetic resonance imaging was used to verify the location from which near-infrared spectroscopy data were obtained through Monte Carlo simulations of photon propagation. Additional clinical assessments of MS disease severity were carried out by trained neurologists. Linear mixed effect models were used to compare cortical oxygenation between cases and controls, and against measures of MS severity. RESULTS: Thirty-three patients with secondary progressive MS (median expanded disability status scale 6 [IQR: 5-6.5]; median age 53.0 [IQR: 49-58]) and 20 age-matched controls were recruited. Modeling of photon propagation confirmed spectroscopy data were obtained from the prefrontal cortex. Patients with SPMS had significantly lower cortical hemoglobin oxygenation compared with controls (-6.0% [95% CI: -10.0 to -1.9], P = 0.004). There were no significant associations between cortical oxygenation and MS severity. INTERPRETATION: Using an advanced, multiwavelength time-domain near-infrared spectroscopy system, we demonstrate that patients with SPMS have lower cortical oxygenation compared with controls.

Learnable real-time inference of molecular composition from diffuse spectroscopy of brain tissue.

Significance: Diffuse optical modalities such as broadband near-infrared spectroscopy (bNIRS) and hyperspectral imaging (HSI) represent a promising alternative for low-cost, non-invasive, and fast monitoring of living tissue. Particularly, the possibility of extracting the molecular composition of the tissue from the optical spectra deems the spectroscopy techniques as a unique diagnostic tool. Aim: No established method exists to streamline the inference of the biochemical composition from the optical spectrum for real-time applications such as surgical monitoring. We analyze a machine learning technique for inference of changes in the molecular composition of brain tissue. Approach: We propose modifications to the existing learnable methodology based on the Beer-Lambert law. We evaluate the method's applicability to linear and nonlinear formulations of this physical law. The approach is tested on data obtained from the bNIRS- and HSI-based monitoring of brain tissue. Results: The results demonstrate that the proposed method enables real-time molecular composition inference while maintaining the accuracy of traditional methods. Preliminary findings show that Beer-Lambert law-based spectral unmixing allows contrasting brain anatomy semantics such as the vessel tree and tumor area. Conclusion: We present a data-driven technique for inferring molecular composition change from diffuse spectroscopy of brain tissue, potentially enabling intra-operative monitoring.

Transportable hyperspectral imaging setup based on fast, high-density spectral scanning for in situ quantitative biochemical mapping of fresh tissue biopsies.

Significance: Histopathological examination of surgical biopsies, such as in glioma and glioblastoma resection, is hindered in current clinical practice by the long time required for the laboratory analysis and pathological screening, typically taking several days or even weeks to be completed. Aim: We propose here a transportable, high-density, spectral scanning-based hyperspectral imaging (HSI) setup, named HyperProbe1, that can provide in situ, fast biochemical analysis, and mapping of fresh surgical tissue samples, right after excision, and without the need for fixing, staining nor compromising the integrity of the tissue properties. Approach: HyperProbe1 is based on spectral scanning via supercontinuum laser illumination filtered with acousto-optic tunable filters. Such methodology allows the user to select any number and type of wavelength bands in the visible and near-infrared range between 510 and 900 nm (up to a maximum of 79) and to reconstruct 3D hypercubes composed of high-resolution (4 to 5 µ m ), widefield images ( 0.9 × 0.9 mm 2 ) of the surgical samples, where each pixel is associated with a complete spectrum. Results: The HyperProbe1 setup is here presented and characterized. The system is applied to 11 fresh surgical biopsies of glioma from routine patients, including different grades of tumor classification. Quantitative analysis of the composition of the tissue is performed via fast spectral unmixing to reconstruct the mapping of major biomarkers, such as oxy-( HbO 2 ) and deoxyhemoglobin (HHb), as well as cytochrome-c-oxidase (CCO). We also provided a preliminary attempt to infer tumor classification based on differences in composition in the samples, suggesting the possibility of using lipid content and differential CCO concentrations to distinguish between lower and higher-grade gliomas. Conclusions: A proof of concept of the performances of HyperProbe1 for quantitative, biochemical mapping of surgical biopsies is demonstrated, paving the way for improving current post-surgical, histopathological practice via non-destructive, in situ streamlined screening of fresh tissue samples in a matter of minutes after excision.

Spatulated anastomosis with continuous suture in microreconstructive surgery.

In a well-proven criterion standard technique commonly used in cardiovascular surgery for anastomosis, proximal and distal vessels are spatulated to increase the anastomotic surface and improve congruency between the 2 vessels. Anastomosis is performed with continuous suture of the 2 bisected extremities.A review of the current literature has confirmed that our preliminary results were similar to those achieved by surgeons using the simple interrupted suture technique for microsurgical anastomosis.Patency is highly satisfactory with this technique for anastomosis. Moreover, it is a reliable technique requiring shorter total operative time. Hemostasis is easy to control and can be used with vessel diameters as small as 1 mm. For all these reasons, this technique already commonly used in vascular surgery for anastomosis could be interesting in microsurgery as well.

Brain temperature monitoring in newborn infants: Current methodologies and prospects.

Brain tissue temperature is a dynamic balance between heat generation from metabolism, passive loss of energy to the environment, and thermoregulatory processes such as perfusion. Perinatal brain injuries, particularly neonatal encephalopathy, and seizures, have a significant impact on the metabolic and haemodynamic state of the developing brain, and thereby likely induce changes in brain temperature. In healthy newborn brains, brain temperature is higher than the core temperature. Magnetic resonance spectroscopy (MRS) has been used as a viable, non-invasive tool to measure temperature in the newborn brain with a reported accuracy of up to 0.2 degrees Celcius and a precision of 0.3 degrees Celcius. This measurement is based on the separation of chemical shifts between the temperature-sensitive water peaks and temperature-insensitive singlet metabolite peaks. MRS thermometry requires transport to an MRI scanner and a lengthy single-point measurement. Optical monitoring, using near infrared spectroscopy (NIRS), offers an alternative which overcomes this limitation in its ability to monitor newborn brain tissue temperature continuously at the cot side in real-time. Near infrared spectroscopy uses linear temperature-dependent changes in water absorption spectra in the near infrared range to estimate the tissue temperature. This review focuses on the currently available methodologies and their viability for accurate measurement, the potential benefits of monitoring newborn brain temperature in the neonatal intensive care unit, and the important challenges that still need to be addressed.

Optical Monitoring in Neonatal Seizures.

BACKGROUND: Neonatal seizures remain a significant cause of morbidity and mortality worldwide. The past decade has resulted in substantial progress in seizure detection and understanding the impact seizures have on the developing brain. Optical monitoring such as cerebral near-infrared spectroscopy (NIRS) and broadband NIRS can provide non-invasive continuous real-time monitoring of the changes in brain metabolism and haemodynamics. AIM: To perform a systematic review of optical biomarkers to identify changes in cerebral haemodynamics and metabolism during the pre-ictal, ictal, and post-ictal phases of neonatal seizures. METHOD: A systematic search was performed in eight databases. The search combined the three broad categories: (neonates) AND (NIRS) AND (seizures) using the stepwise approach following PRISMA guidance. RESULTS: Fifteen papers described the haemodynamic and/or metabolic changes observed with NIRS during neonatal seizures. No randomised controlled trials were identified during the search. Studies reported various changes occurring in the pre-ictal, ictal, and post-ictal phases of seizures. CONCLUSION: Clear changes in cerebral haemodynamics and metabolism were noted during the pre-ictal, ictal, and post-ictal phases of seizures in neonates. Further studies are necessary to determine whether NIRS-based methods can be used at the cot-side to provide clear pathophysiological data in real-time during neonatal seizures.

Multi-laboratory performance assessment of diffuse optics instruments: the BitMap exercise.

SIGNIFICANCE: Multi-laboratory initiatives are essential in performance assessment and standardization-crucial for bringing biophotonics to mature clinical use-to establish protocols and develop reference tissue phantoms that all will allow universal instrument comparison. AIM: The largest multi-laboratory comparison of performance assessment in near-infrared diffuse optics is presented, involving 28 instruments and 12 institutions on a total of eight experiments based on three consolidated protocols (BIP, MEDPHOT, and NEUROPT) as implemented on three kits of tissue phantoms. A total of 20 synthetic indicators were extracted from the dataset, some of them defined here anew. APPROACH: The exercise stems from the Innovative Training Network BitMap funded by the European Commission and expanded to include other European laboratories. A large variety of diffuse optics instruments were considered, based on different approaches (time domain/frequency domain/continuous wave), at various stages of maturity and designed for different applications (e.g., oximetry, spectroscopy, and imaging). RESULTS: This study highlights a substantial difference in hardware performances (e.g., nine decades in responsivity, four decades in dark count rate, and one decade in temporal resolution). Agreement in the estimates of homogeneous optical properties was within 12% of the median value for half of the systems, with a temporal stability of <5 % over 1 h, and day-to-day reproducibility of <3 % . Other tests encompassed linearity, crosstalk, uncertainty, and detection of optical inhomogeneities. CONCLUSIONS: This extensive multi-laboratory exercise provides a detailed assessment of near-infrared Diffuse optical instruments and can be used for reference grading. The dataset-available soon in an open data repository-can be evaluated in multiple ways, for instance, to compare different analysis tools or study the impact of hardware implementations.

Absolute quantification of cerebral tissue oxygen saturation with multidistance broadband NIRS in newborn brain.

Tissue oximetry with near-infrared spectroscopy (NIRS) is a technique for the measurement of absolute tissue oxygen saturation (StO2). Offering a real-time and non-invasive assessment of brain oxygenation and haemodynamics, StO2 has potential to be used for the assessment of newborn brain injury. Multiple algorithms have been developed to measure StO2, however, issues with low measurement accuracy or extracranial tissue signal contamination remain. In this work, we present a novel algorithm to recover StO2 in the neonate, broadband multidistance oximetry (BRUNO), based on a measurement of the gradient of attenuation against distance measured with broadband NIRS. The performance of the algorithm was compared to two other published algorithms, broadband fitting (BF) and spatially resolved spectroscopy (SRS). The median error when recovering StO2 in light transport simulations on a neonatal head mesh was 0.4% with BRUNO, 4.2% with BF and 9.5% with SRS. BRUNO was more sensitive to brain tissue oxygenation changes, shown in layered head model simulations. Comparison of algorithm performance during full oxygenation-deoxygenation cycles in a homogeneous dynamic blood phantom showed significant differences in the dynamic range of the algorithms; BRUNO recovered StO2 over 0-100%, BF over 0-90% and SRS over 39-80%. Recovering StO2 from data collected in a neonate treated at the neonatal intensive care showed different baseline values; mean StO2 was 64.9% with BRUNO, 67.2% with BF and 73.2% with SRS. These findings highlight the effect of StO2 algorithm selection on oxygenation recovery; applying BRUNO in the clinical care setting could reveal further insight into complex haemodynamic processes occurring during neonatal brain injury.

Role of Optical Neuromonitoring in Neonatal Encephalopathy-Current State and Recent Advances.

Neonatal encephalopathy (NE) in term and near-term infants is a significant global health problem; the worldwide burden of disease remains high despite the introduction of therapeutic hypothermia. Assessment of injury severity and effective management in the neonatal intensive care unit (NICU) relies on multiple monitoring modalities from systemic to brain-specific. Current neuromonitoring tools provide information utilized for seizure management, injury stratification, and prognostication, whilst systemic monitoring ensures multi-organ dysfunction is recognized early and supported wherever needed. The neuromonitoring technologies currently used in NE however, have limitations in either their availability during the active treatment window or their reliability to prognosticate and stratify injury confidently in the early period following insult. There is therefore a real need for a neuromonitoring tool that provides cot side, early and continuous monitoring of brain health which can reliably stratify injury severity, monitor response to current and emerging treatments, and prognosticate outcome. The clinical use of near-infrared spectroscopy (NIRS) technology has increased in recent years. Research studies within this population have also increased, alongside the development of both instrumentation and signal processing techniques. Increasing use of commercially available cerebral oximeters in the NICU, and the introduction of advanced optical measurements using broadband NIRS (BNIRS), frequency domain NIRS (FDNIRS), and diffuse correlation spectroscopy (DCS) have widened the scope by allowing the direct monitoring of oxygen metabolism and cerebral blood flow, both key to understanding pathophysiological changes and predicting outcome in NE. This review discusses the role of optical neuromonitoring in NE and why this modality may provide the next significant piece of the puzzle toward understanding the real time state of the injured newborn brain.

Time-domain NIRS system based on supercontinuum light source and multi-wavelength detection: validation for tissue oxygenation studies.

We present and validate a multi-wavelength time-domain near-infrared spectroscopy (TD-NIRS) system that avoids switching wavelengths and instead exploits the full capability of a supercontinuum light source by emitting and acquiring signals for the whole chosen range of wavelengths. The system was designed for muscle and brain oxygenation monitoring in a clinical environment. A pulsed supercontinuum laser emits broadband light and each of two detection modules acquires the distributions of times of flight of photons (DTOFs) for 16 spectral channels (used width 12.5 nm / channel), providing a total of 32 DTOFs at up to 3 Hz. Two emitting fibers and two detection fiber bundles allow simultaneous measurements at two positions on the tissue or at two source-detector separations. Three established protocols (BIP, MEDPHOT, and nEUROPt) were used to quantitatively assess the system's performance, including linearity, coupling, accuracy, and depth sensitivity. Measurements were performed on 32 homogeneous phantoms and two inhomogeneous phantoms (solid and liquid). Furthermore, measurements on two blood-lipid phantoms with a varied amount of blood and Intralipid provide the strongest validation for accurate tissue oximetry. The retrieved hemoglobin concentrations and oxygen saturation match well with the reference values that were obtained using a commercially available NIRS system (OxiplexTS) and a blood gas analyzer (ABL90 FLEX), except a discrepancy occurs for the lowest amount of Intralipid. In-vivo measurements on the forearm of three healthy volunteers during arterial (250 mmHg) and venous (60 mmHg) cuff occlusions provide an example of tissue monitoring during the expected hemodynamic changes that follow previously well-described physiologies. All results, including quantitative parameters, can be compared to other systems that report similar tests. Overall, the presented TD-NIRS system has an exemplary performance evaluated with state-of-the-art performance assessment methods.