New frontiers in time-domain diffuse optics, a review

The recent developments in time-domain diffuse optics that rely on physical concepts (e.g., time-gating and null distance) and advanced photonic components (e.g., vertical cavity source-emitting laser as light sources, single photon avalanche diode, and silicon photomultipliers as detectors, fast-gating circuits, and time-to-digital converters for acquisition) are focused. This study shows how these tools could lead on one hand to compact and wearable time-domain devices for point-of-care diagnostics down to the consumer level and on the other hand to powerful systems with exceptional depth penetration and sensitivity

A novel approach to monitor tissue oxygen saturation with broadband near-infrared spectroscopy

Cerebral oximetry is the measurement of tissue oxygen saturation, StO2, with near-infrared spectroscopy (NIRS). The technique offers a non-invasive assessment of cerebral oxygenation and has potential to be used as a biomarker in neonatal critical care, particularly hypoxic-ischaemic-encephalopathy (HIE). HIE is a major cause of neonatal mortality and affected neonates need continuous cerebral monitoring to guide treatment and improve patient outcome. While multiple algorithms to recover StO2 have been published, issues with low measurement accuracy or extracranial tissue signal contamination remain. This thesis is focused on the exploration of recovering StO2 from continuous-wave broadband NIRS measurements with the aim to develop a novel algorithm to recover StO2 with increased dynamic range and depth resolution. The novel algorithm, broadband multidistance oximetry (BRUNO), recovers StO2 from a broadband multidistance measurement of the attenuation slope against distance. BRUNO combines and expands two other StO2 algorithms, spatially resolved spectroscopy (SRS) and broadband fitting (BF). The evaluation of algorithm performance was done in data obtained in computational simulations and phantoms. The median error of brain StO2 recovered in simulations of brain and extracerebral tissue oxygenation changes was 1.1% with BRUNO, 2.3% with BF and 3.8% with SRS. Measurements during full oxygenation-deoxygenation cycles in a homogeneous blood phantom showed differences in the dynamic range of the algorithms; BRUNO recovered StO2 over 0–100%, BF over 0–90% and SRS over 40–80%. These results show higher accuracy of BRUNO StO2, higher sensitivity to brain oxygenation and wider dynamic range. Measurements of StO2 in one neonate with HIE showed that the StO2 algorithms led to different baseline values. Including an automated data assessment step in BRUNO to evaluate the suitability of collected spectra for analysis ensured BRUNO reliability. 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 oxygenation processes occurring during neonatal brain injury

Development of optical instrumentation and methods to monitor brain oxygen metabolism: application to neonatal brain injury

Hypoxic ischemic encephalopathy (HIE) is a relatively common and potentially devastating form of perinatal brain injury, associated with neurodevelopmental problems and mortality. HIE is an evolving process. There is a need for real-time, in-vivo measurements of brain oxygenation and metabolism for clinical assessment in the first days of life, to detect those at risk of further brain injury who may benefit from redirection of care. This thesis describes the development of a broadband near-infrared spectroscopy (NIRS) system to monitor changes in metabolism and haemodynamics in HIE infants at the cotside. This system uses multiple wavelengths (λ=136,770-905nm) to monitor changes in concentration of the oxidation state of cytochrome-c-oxidase (oxCCO) as well as haemoglobin oxygenation. Changes in oxCCO are indicative of CCO redox state changes within mitochondria and therefore represent oxygen utilization. The 2-channel system incorporates a broadband source, optical fibres, spectrograph and CCD. This set up is flexible and robustly monitors changes in haemoglobin and oxCCO. The system was developed specifically for the neonatal intensive care unit (NICU) and has been demonstrated on 38 brain-injured newborn infants (28 with HIE). Data was continuously collected over the frontal lobe simultaneously with systemic data for multimodal analysis. This allows the study of cerebral changes in response to global pathophysiological events. HIE was assessed by magnetic resonance spectroscopy measurement of lactate to NAA ratio (Lac/NAA), the gold standard for neurodevelopmental outcome. Initially the analysis focussed on spontaneous hypoxias. The relationship between haemoglobin oxygenation and oxCCO during hypoxic events was significantly associated with Lac/NAA (n=22,r=0.51,p=0.02). Further investigation of the dynamics of the cerebral changes during hypoxias found oxCCO differences with injury severity (not observed in haemoglobins). Finally, the relationship between cerebral signals and systemic physiology was investigated with a multivariate statistical technique. A strong relationship between oxCCO and systemic changes indicated severe brain injury (n=12,p=0.04)

The Effects of an Extracorporeal Circulation on Cerebral Perfusion during Paediatric Critical Care and Cardiothoracic Procedures

The developing brain is highly vulnerable to physiological and pharmacological insults, which can impact cerebral blood flow (CBF), resulting in neurological deficit. Within the clinical environment, a group of patients at particular risk of neurological insult are those who require an extracorporeal circulation. This has a profound effect on CBF due to the use of non-pulsatile blood flow, pharmacological agents and periods of hypo/hyperperfusion. As a result, effective cerebral monitoring is essential to prevent periods of ischaemia and subsequently, enhance quality of life in survivors. Patients requiring an extracorporeal circulation include those treated for acute respiratory and/or cardiac failure using extracorporeal membrane oxygenation (ECMO), and the use of cardiopulmonary bypass (CPB) during cardiac surgery for congenital heart defects. The overarching aim of this thesis was to examine how an extracorporeal circulation impacts cerebral perfusion throughout the entire treatment process and following recovery in paediatric intensive care. Measurements of cerebral perfusion used throughout the thesis are described in the experimental methods chapter. These include transcranial doppler ultrasound (TCD) and near infrared spectroscopy (NIRS). Another aim of the experimental chapter was to collect TCD data and compare the values to previously published research. Measurements were taken in a ‘healthy’ neonatal population and then compared to previously published age-matched comparisons. Measurements were also taken in clinically ill patients and then compared to values from previously published ventilated population. Values were comparable to previously published data which suggested the TCD operator was proficient in isonating the middle cerebral artery (MCA). An observational study was conducted using TCD to measure CBFv at multiple time points during ECMO with a focus on the weaning period in a paediatric population. Fourteen patients that underwent veno-arterial (V-A) ECMO were enrolled. Eight (mean age 69 days) had central cannulation for post-cardiac surgery support, while six (mean age 84 days) had neck cannulation for respiratory support. CBFv was measured from the MCA during weaning at several time points: full flow ECMO, ¾ flow, ½ flow, ¼ flow, minimum flow, when off ECMO and post decannulation. NIRS, blood pressure, heart rate and arterial oxygen saturation were recorded at the same time points. During the first 5 days of full flow ECMO, CBFv remained relatively stable (p=0.54). During weaning, those that successfully decannulated had on average a higher CBFv of 9.1 cm/s compared to those that failed weaning. From the patients decannulated, those receiving conventional treatment had an average higher CBFv of 9.9 cm/s compared to patients on high frequency oscillatory ventilation. Overall, the relationship between NIRS and TCD was positive but weak. Another study was undertaken to examine CBFv and an extracorporeal circulation during aortic arch repair. Neonates requiring aortic arch repair are unable to maintain adequate oxygenation levels and require surgical intervention. A high percentage of survivor’s exhibit signs of neurological deficit possibly due to inadequate CBF during surgery. The aim was to continuously monitor MCA velocity (MCAv) during surgery. A secondary aim was to examine the impact of temperature on CBF, with cooling ranging from 18 to 25°C based on surgeon preference. MCAv was monitored in 24 neonates (age 19±6 days, body mass 3.6±0.6 kg) undergoing surgery on the aortic arch, alongside NIRS, blood pH, pO2, pCO2, HCO3, lactate, Hb, Htc (%) and temperature (core and rectal). Using general linear models, MCAv was compared at several time points. These included: initial sedation; cardiopulmonary bypass (CBP); cooling at 30°c, 25°c, the lowest temperature; during selective cerebral perfusion; whole body perfusion; rewarming at 25°c, 30°c, 36°c; off cardiopulmonary bypass; and after surgery. During and following surgery, MCAv was lower compared to previously published healthy age-matched controls, except during cooling period. CBFv increased during cooling at 30°c, 25°c and the lowest temperature respectively when compared to CBP (p=0.03). Once off CBP, MCAv returned to pre-surgery values. No significant difference was noted between patients cooled to 20 or 25°c. Overall, this thesis provides evidence of disruptions in cerebral perfusion during different stages of treatments involving an extracorporeal circulation. The current clinical tool for monitoring cerebral perfusion is NIRS, which may not provide sufficiently sensitive data on cerebral perfusion during treatments using an extracorporeal circulation. Taken together, the findings provide important data for clinicians treating paediatric patients requiring an extracorporeal circulation. It provides data identifying specific time periods of reduced cerebral perfusion, while highlighting limitations of current methods of monitoring

Brain Injury

The present two volume book "Brain Injury" is distinctive in its presentation and includes a wealth of updated information on many aspects in the field of brain injury. The Book is devoted to the pathogenesis of brain injury, concepts in cerebral blood flow and metabolism, investigative approaches and monitoring of brain injured, different protective mechanisms and recovery and management approach to these individuals, functional and endocrine aspects of brain injuries, approaches to rehabilitation of brain injured and preventive aspects of traumatic brain injuries. The collective contribution from experts in brain injury research area would be successfully conveyed to the readers and readers will find this book to be a valuable guide to further develop their understanding about brain injury

Development of a portable time-domain system for diffuse optical tomography of the newborn infant brain

Conditions such as hypoxic-ischaemic encephalopathy (HIE) and perinatal arterial ischaemic stroke (PAIS) are causes of lifelong neurodisability in a few hundred infants born in the UK each year. Early diagnosis and treatment are key, but no effective bedside detection and monitoring technology is available. Non-invasive, near-infrared techniques have been explored for several decades, but progress has been inhibited by the lack of a portable technology, and intensity measurements, which are strongly sensitive to uncertain and variable coupling of light sources and detector to the scalp. A technique known as time domain diffuse optical tomography (TD-DOT) uses measurements of photon flight times between sources and detectors placed on the scalp. Mean flight time is largely insensitive to the coupling and variation in mean flight time can reveal spatial variation in blood volume and oxygenation in regions of brain sampled by the measurements. While the cost, size and high power consumption of such technology have hitherto prevented development of a portable imaging system, recent advances in silicon technology are enabling portable and low-power TD-DOT devices to be built. A prototype TD-DOT system is proposed and demonstrated, with the long-term aim to design a portable system based on independent modules, each supporting a time-of-flight detector and a pulsed source. The operation is demonstrated of components that can be integrated in a portable system: silicon photodetectors, integrated circuit-based signal conditioning and time detection -- built using a combination of off-the-shelf components and reconfigurable hardware, standard computer interfaces, and data acquisition and calibration software. The only external elements are a PC and a pulsed laser source. This thesis describes the design process, and results are reported on the performance of a 2-channel system with online histogram generation, used for phantom imaging. Possible future development of the hardware is also discussed

New Horizons in Time-Domain Diffuse Optical Spectroscopy and Imaging

Jöbsis was the first to describe the in vivo application of near-infrared spectroscopy (NIRS), also called diffuse optical spectroscopy (DOS). NIRS was originally designed for the clinical monitoring of tissue oxygenation, and today it has also become a useful tool for neuroimaging studies (functional near-infrared spectroscopy, fNIRS). However, difficulties in the selective and quantitative measurements of tissue hemoglobin (Hb), which have been central in the NIRS field for over 40 years, remain to be solved. To overcome these problems, time-domain (TD) and frequency-domain (FD) measurements have been tried. Presently, a wide range of NIRS instruments are available, including commonly available commercial instruments for continuous wave (CW) measurements, based on the modified Beer–Lambert law (steady-state domain measurements). Among these measurements, the TD measurement is the most promising approach, although compared with CW and FD measurements, TD measurements are less common, due to the need for large and expensive instruments with poor temporal resolution and limited dynamic range. However, thanks to technological developments, TD measurements are increasingly being used in research, and also in various clinical settings. This Special Issue highlights issues at the cutting edge of TD DOS and diffuse optical tomography (DOT). It covers all aspects related to TD measurements, including advances in hardware, methodology, the theory of light propagation, and clinical applications

The bioenergetic and redox phenotype in human critical illness

A multitude of pathologies may progress to a state called ‘critical illness’, the hallmark of which is multiple organ failure. Supportive therapy is based on the hypothesis that organ failure results from bioenergetic collapse but attempts to restore energetic capacity through augmentation of systemic oxygen transport have failed to improve survival. The potential relevance of cellular adaptation for survival in critical illness has not been considered. This thesis explored the hypothesis that survival from critical illness could be related to dynamic changes in cellular bioenergetic and redox phenotype. Instead of bioenergetic collapse, skeletal muscle from critically ill patients demonstrated a profile of modifications consistent with cellular hypoxic adaptation, including: greater coupling efficiency of oxidative phosphorylation; selective reduction in respiratory capacity supported by complex I and fatty acid oxidation (FAO), accompanied by a switch from the tricarboxylic acid cycle towards glycolysis, and downstream impairment in FAO and accumulation of medium and long chain carnitines, in comparison to reference patients. The overall redox status in skeletal muscle was more reduced in in critically ill patients than reference patients, suggesting an enhanced reductive drive. Survivors and non survivors exhibited distinct phenotypes, the nature of which were time-specific. Within 48 hours of developing organ failure, survivors had lower skeletal muscle complex I capacity and lower plasma antioxidant capacity, but 7 days later these differences had resolved, and survivors now demonstrated lower plasma lipid peroxidation than non survivors. Specific bioenergetic modifications in skeletal muscle and plasma redox status in critical illness were related to aspects of microcirculatory function but not systemic indices of oxygenation. Dynamic adaptation in microscopic biological functions, such as bioenergetics, metabolism and redox, may underpin human resilience to life-threatening stress. This work calls for further investigation into cell-based strategies of human life-support