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Articles by Ilias Tachtsidis in JoVE

 JoVE Behavior

Using Fiberless, Wearable fNIRS to Monitor Brain Activity in Real-world Cognitive Tasks

1Department of Medical Physics and Biomedical Engineering, Malet Place Engineering Building, University College London, 2Infrared Imaging Lab, Institute for Advanced Biomedical Technology (ITAB), Department of Neuroscience, Imaging and Clinical Sciences, University of Chieti-Pescara, 3Institute of Cognitive Neuroscience, Alexandra House, University College London

JoVE 53336

Other articles by Ilias Tachtsidis on PubMed

Measurement of the Optical Properties of the Adult Human Head with Spatially Resolved Spectroscopy and Changes of Posture

Advances in Experimental Medicine and Biology. 2003  |  Pubmed ID: 15174596

Spectral Characteristics of Spontaneous Oscillations in Cerebral Haemodynamics Are Posture Dependent

Advances in Experimental Medicine and Biology. 2003  |  Pubmed ID: 15174599

Investigation of Cerebral Haemodynamics by Near-infrared Spectroscopy in Young Healthy Volunteers Reveals Posture-dependent Spontaneous Oscillations

Physiological Measurement. Apr, 2004  |  Pubmed ID: 15132309

Autonomic reflexes enable the cardiovascular system to respond to gravitational displacement of blood during changes in posture. Spontaneous oscillations present in the cerebral and systemic circulation of healthy subjects have demonstrated a regulatory role. This study assessed the dynamic responses of the cerebral and systemic circulation upon standing up and the posture dependence of spontaneous oscillations. In ten young healthy volunteers, blood pressure and cerebral haemodynamics were continuously monitored non-invasively using the Portapres and near-infrared spectroscopy (NIRS), respectively. Oscillatory changes in the cerebral NIRS signals and the diastolic blood pressure (DBP) signal have been identified by the fast Fourier analysis. Blood pressure increased during standing and returned to basal level when volunteers sat on a chair. The mean value of cerebral tissue oxygen index (TOI) as measured by NIRS did not demonstrate any significant changes. Oscillatory changes in DBP, oxyhaemoglobin concentration [O2Hb] and TOI showed a significant increase when subjects were standing. Investigation of the low frequency component (approximately 0.1 Hz) of these fluctuations revealed posture dependence associated with activation of autonomic reflexes. Systemic and cerebral changes appeared to preserve adequate blood flow and cerebral perfusion during standing in healthy volunteers. Oscillatory changes in [O2Hb] and TOI, which may be related to the degree of cerebral sympathetic stimulation, are posture dependent in healthy subjects.

A Physiological Model of Cerebral Blood Flow Control

Mathematical Biosciences. Apr, 2005  |  Pubmed ID: 15854674

The construction of a computational model of the human brain circulation is described. We combine an existing model of the biophysics of the circulatory system, a basic model of brain metabolic biochemistry, and a model of the functioning of vascular smooth muscle (VSM) into a single model. This represents a first attempt to understand how the numerous different feedback pathways by which cerebral blood flow is controlled interact with each other. The present work comprises the following: Descriptions of the physiology underlying the model; general comments on the processes by which this physiology is translated into mathematics; comments on parameter setting; and some simulation results. The simulations presented are preliminary, but show qualitative agreement between model behaviour and experimental results.

Rate of Change in Cerebral Oxygenation and Blood Pressure in Response to Passive Changes in Posture: a Comparison Between Pure Autonomic Failure Patients and Controls

Advances in Experimental Medicine and Biology. 2005  |  Pubmed ID: 16594152

The cardiovascular and cerebrovascular responses to head-up postural change are compromised in pure autonomic failure (PAF) patients because of sympathetic denervation. The aim of this study was to characterize the rate of change of systemic mean blood pressure (MBP) and cerebral haemodynamics in response to passive posture changes. Nine PAF patients and 9 age-matched controls took part in this study. MBP and oxy- (O2Hb), deoxy-haemoglobin (HHb), and tissue oxygenation index (TOI) on the forehead were continuously monitored non-invasively using the Portapres and near-infrared spectroscopy (NIRS), respectively. From visual inspection of the haemoglobin difference signal (Hb(diff) = O2Hb-HHb), seven distinct phases were marked (1: supine, 2: start passive tilt, 3: head up to 60 degrees degrees, 4: end of tilt, 5: tilt reversal, 6: return to supine, 7: rest); the same time points were used for all of the other signals. For each phase, the slope was calculated using a linear regression algorithm. Significant differences were found between PAF patients and controls in the Hb(diff) slope magnitudes for phases 3 (P < .05) and 5 (P = .01), and the duration of phase 2 (P < .05). MBP slope magnitudes showed significant differences for phases 2 (P < .01) and 5 (P < .01). These differences in the rate of change suggest differences in blood vessel resistance related to sympathetic activation.

Circulation Time in Man from Lung to Periphery As an Indirect Index of Cardiac Output

Advances in Experimental Medicine and Biology. 2005  |  Pubmed ID: 16594167

Circulation time (Ct) between lung and periphery may be a surrogate for cardiac output, estimated here, for the most part, as the time between taking a breath of nitrogen and peripheral detection of a desaturation pulse. Use of pulse oximetry involves an internal, instrument delay; however, using the ear, we found shortening with exercise (12.1 +/- 0.37 sec, at rest; 9.1 +/- 0.25 sec at 100 watts), lengthening after beta-blockade, and lengthening in patients with echocardiographic and clinical left heart failure (8 patients 16.2 +/- 1.1 sec; 6 controls 12.0 +/- 0.5 sec). Pulse oximetry failed, however, to discriminate heart failure from normal in several patients. In patients referred to a department of nuclear medicine for assessment of chest pain, pulse oximetry (finger and ear) showed unacceptable variability. Nuclide delays between lung and carotid artery correlated significantly with the reciprocal of gated SPECT estimated cardiac output (Q(gs)); not so, however, for lung to finger. In normal subjects, an old Waters fast response oximeter gave short, reproducible Ct estimates and a significant correlation with the reciprocal of (indirect Fick) cardiac output (Q(if)). The relationship for normal subjects was: Ct = 0.28 x 60/Q(if) + 2.8 sec (Q(if) in L min.; P slope < .001).

Measurement of the Absolute Optical Properties and Cerebral Blood Volume of the Adult Human Head with Hybrid Differential and Spatially Resolved Spectroscopy

Physics in Medicine and Biology. Feb, 2006  |  Pubmed ID: 16424590

A hybrid differential and spatially resolved spectroscopy (SRS) technique has been developed to measure absolute absorption coefficient (mu(a)), reduced scattering coefficient (mu'(s)) and cerebral blood volume (CBV) in the adult human head. A spectrometer with both differential and SRS capabilities has been used to carry out measurements in 12 subjects. Two versions of the calculation have been considered using the hybrid technique, with one considering water as a chromophore as well as oxy- and deoxy-haemoglobin, and one ignoring water. The CBV has also been measured using a previously described technique based on changing the arterial saturation (SaO(2)) measured separately by a pulse oximeter, resulting in mean +/- SD CBV(a) (intra-individual coefficient of variation) = 2.22 +/- 1.06 ml/100 g (29.9%). (The superscript on CBV indicates the different calculation basis.) Using the hybrid technique with water ignored, CBV(0) = 3.18 +/- 0.73 ml/100 g (10.0%), mu(0)(a)(813 nm) = 0.010 +/- 0.003 mm(-1) and mu'(0)(s)(813 nm) = 1.19 +/- 0.55 mm(-1) (data quoted at 813 nm). With water considered, CBV(w) = 3.05 +/- 0.77 ml/100 g (10.5%), mu(w)(a)(813 nm) = 0.010 +/- 0.003 mm(-1) and mu'(w)(s)(813 nm) = 1.28 +/- 0.56 mm(-1). The mean biases between CBV(0)/CBV(w), CBV(0)/CBV(a) and CBV(w)/CBV(a) are 0.14 +/- 0.09, 0.79 +/- 1.22 and 0.65 +/- 1.24 ml/100 g. The mean biases between mu(0)(a)(813 nm)/mu(w)(a)(813 nm) and mu'(0)(s)(813 nm)/mu'(w)(s)(813 nm) are (5.9 +/- 10.0) x 10(-4) mm(-1) and -0.084 +/- 0.266 mm(-1), respectively. The method we describe extends the functionality of the current SRS instrumentation.

Changes in Cerebral Oxygenation and Haemodynamics During Postural Blood Pressure Changes in Patients with Autonomic Failure

Physiological Measurement. Sep, 2006  |  Pubmed ID: 16868345

Patients with autonomic failure suffer severe postural hypotension that may be associated with symptoms of cerebral hypoperfusion. This study utilized near-infrared spectroscopy (NIRS) to measure changes in cerebral oxygenation and haemodynamics during the head-up tilt table test in 18 patients with autonomic failure and 10 healthy age-matched volunteers. Heart rate, blood pressure (MAP), oxygen saturation, cerebral tissue oxygen index (TOI) and total cerebral haemoglobin concentration [HbT] were measured continuously. In patients with autonomic failure there was a mean (SD) reduction in MAP of 46.7 (26.5) mmHg (p < 0.005) associated with a reduction in TOI of 8.6 (6.2)% (p < 0.005) during the head-up tilt table test. In healthy volunteers mean (SD) MAP rose by 12.3 (8.0) mmHg (p < 0.005) and TOI fell by 2.6 (3.2)% (p < 0.05). There was a mean (SD) reduction in [HbT] of 3.09 (2.82) micromol l(-1) (p < 0.005) in patients, equivalent to a decrease in cerebral blood volume of 0.2 (0.18) ml/100 g. There were no changes in [HbT] in the healthy volunteers. Postural hypotension in patients with autonomic failure is associated with a substantial decrease in absolute cerebral oxygenation measured by NIRS and this might reflect a critical reduction in cerebral oxygen delivery.

Investigation of Oxygen Saturation Derived from Cardiac Pulsations Measured on the Adult Head Using NIR Spectroscopy

Advances in Experimental Medicine and Biology. 2006  |  Pubmed ID: 16927695

Quantification of Adult Cerebral Blood Volume Using the NIRS Tissue Oxygenation Index

Advances in Experimental Medicine and Biology. 2006  |  Pubmed ID: 16927699

Theoretical Investigation of Measuring Cerebral Blood Flow in the Adult Human Head Using Bolus Indocyanine Green Injection and Near-infrared Spectroscopy

Applied Optics. Apr, 2007  |  Pubmed ID: 17356602

To investigate the accuracy of measuring cerebral blood flow (CBF) using a bolus injection of Indocyanine Green (ICG) detected by near-infrared spectroscopy in adult human heads, simulations were performed using a two-layered model representing the extracerebral and intracerebral layers. Modeled optical data were converted into tissue ICG concentration using either the one-detector modified Beer-Lambert law (MBLL) method, or the two-detector partial path-length (PPL) method. The CBFs were estimated using deconvolution and blood flow index techniques. Using the MBLL method, the CBFs were significantly underestimated but the PPL method improved their accuracy and robustness, especially when used as relative measures. The dispersion of the arterial input function also affected the CBF estimates.

Near-infrared Spectroscopic Quantification of Changes in the Concentration of Oxidized Cytochrome C Oxidase in the Healthy Human Brain During Hypoxemia

Journal of Biomedical Optics. Mar-Apr, 2007  |  Pubmed ID: 17477717

The near-IR cytochrome c oxidase (CCO) signal has potential as a clinical marker of changes in mitochondrial oxygen utilization. We examine the CCO signal response to reduced oxygen delivery in the healthy human brain. We induced a reduction in arterial oxygen saturation from baseline levels to 80% in eight healthy adult humans, while minimizing changes in end tidal carbon dioxide tension. We measured changes in the cerebral concentrations of oxidized CCO (Delta[oxCCO]), oxyhemoglobin (Delta[HbO(2)]), and deoxyhemoglobin (Delta[HHb]) using broadband near-IR spectroscopy (NIRS), and estimated changes in cerebral oxygen delivery (ecDO(2)) using pulse oximetry and transcranial Doppler ultrasonography. Results are presented as median (interquartile range). At the nadir of hypoxemia ecDO(2) decreased by 9.2 (5.4 to 12.1)% (p<0.0001), Delta[oxCCO] decreased by 0.24 (0.06 to 0.28) micromoles/l (p<0.01), total hemoglobin concentration increased by 2.83 (2.27 to 4.46) micromoles/l (p<0.0001), and change in hemoglobin difference concentration (Delta[Hbdiff]=Delta[HbO(2)]-Delta[HHb]) decreased by 12.72 (11.32 to 16.34) micromoles/l (p<0.0001). Change in ecDO(2) correlated with Delta[oxCCO] (r=0.78, p<0.001), but not with either change in total hemoglobin concentration or Delta[Hbdiff]. This is the first description of cerebral Delta[oxCCO] during hypoxemia in healthy adults. Studies are ongoing to investigate the clinical relevance of this signal in patients with traumatic brain injury.

Investigation of Frontal Cortex, Motor Cortex and Systemic Haemodynamic Changes During Anagram Solving

Advances in Experimental Medicine and Biology. 2008  |  Pubmed ID: 18290310

We have previously reported changes in the concentrations of oxy-(delta[HbO2]) deoxy- (delta[HHb]) and total haemoglobin (delta[HbT] = delta[HbO2] + delta[HHb]) measured using near infrared spectroscopy (NIRS) over the frontal cortex (FC) during an anagram solving task. These changes were associated with a significant increase in both mean blood pressure (MBP) and heart rate (HR). The aim of this study was to investigate whether the changes in MBP previously recorded during an anagram solving task produces associated changes in scalp blood flow (flux) measured by laser Doppler and whether any changes are seen in NIRS haemodynamic measurements over a control region of the brain (motor cortex: MC). During the 4-Letter anagram task significant changes were observed in the delta[HbO2], delta[HHb] and delta[HbT] in both the frontal and motor cortex (n = 11, FC p < 0.01, MC p < 0.01). These changes were accompanied by significant changes in both MBP (n = 11, p < 0.01) and scalp flux (n = 9, p = 0.01). During the 7-Letter anagram task significant changes were observed in the delta[HbO2] and delta[HbT] (n = 11, FC p < 0.01, MC p < 0.01), which were accompanied by significant changes in both MBP (n = 11, p = 0.05) and flux (n = 9, p = 0.05). The task-related changes seen in MBP and flux in this study appear to contribute to the changes in the NIRS signals over both the activated and control regions of the cortex.

Changes in the Attenuation of Near Infrared Spectra by the Healthy Adult Brain During Hypoxaemia Cannot Be Accounted for Solely by Changes in the Concentrations of Oxy- and Deoxy-haemoglobin

Advances in Experimental Medicine and Biology. 2008  |  Pubmed ID: 18290332

It has been suggested that changes in oxidised cytochrome c oxidase concentration ([oxCCO]) measured using cerebral near infrared spectroscopy (NIRS) may be algorithm artefacts. We examine the change in near infrared (NIR) attenuation by the healthy adult brain (n = 10) during hypoxaemia. Broadband spectroscopic data were collected during normoxia, and hypoxaemia. The UCLn algorithm was used to fit (a) oxy- (HbO2) and deoxy-haemoglobin (HHb) spectra (2 component fit), and (b) HbO2, HHb and oxidised-reduced cytochrome c oxidase difference spectra (3 component fit) to the mean change in NIR attenuation between baseline and hypoxaemia. The sum of squares of the residuals was 100 x 10(-7) OD2 for the 2 component fit and 8 x 10(-7) OD2 for the 3 component fit, and the two sets of residuals differed from each other (p = 0.0003). We compare experimental and simulated data and suggest that the 2 component residuals indicate a change in [oxCCO]. Changes in near infrared attenuation by the healthy adult brain during hypoxaemia cannot be accounted for solely by changes in oxy- and deoxy-haemoglobin concentrations. Including [oxCCO] in the algorithm improves its fit quality. These data suggest that changes in cerebral cytochrome c oxidase redox occur during hypoxaemia and that they can be detected using NIRS.

Cerebral Tissue Oxygen Saturation Calculated Using Low Frequency Haemoglobin Oscillations Measured by Near Infrared Spectroscopy in Adult Ventilated Patients

Advances in Experimental Medicine and Biology. 2008  |  Pubmed ID: 18290334

Oxy- (HbO2) and deoxy- (HHb) haemoglobin signals measured by near infrared (NIR) spectroscopy over the human frontal lobes frequently contain respiratory and low frequency oscillations (LFOs). It has been suggested previously that venous oxygen saturation (SvO2) can be calculated from these respiratory oscillations. In this paper, we investigated the use of a Fourier transform based algorithm to calculate an oxygen saturation measure known as S(osc)O2 which may be a close estimate of the underlying SvO2. S(osc)O2 was calculated using three different frequency ranges, (1) respiratory oscillations only, (2) LFOs only, and (3) both respiratory oscillations and LFOs. At each frequency range S(osc)O2 was calculated using either (1) the modified Beer-Lambert law (MBL) or (2) spatially resolved spectroscopy (SRS). In total six different measurements of S(osc)O2 were investigated here. Experiments were performed in six adult ventilated patients with traumatic brain injury. The patients' inspired oxygen fraction (FiO2) was raised in two hyperoxic phases. The calculated S(osc)O2 values were compared with other cerebral oxygenation measures including an intraparenchymal catheter based brain tissue oxygen tension (PbrO2) and the NIR based tissue oxygenation index (TOI). It was found that the S(osc)O2 calculated using the combined respiratory and LFO frequency range and the SRS method resulted in the highest detection rates of hyperoxic changes. This measure of S(osc)O2 may provide a viable, continuous, non invasive, bedside measure of cerebral venous oxygen saturation.

Measurement of Cerebral Tissue Oxygenation in Young Healthy Volunteers During Acetazolamide Provocation: a Transcranial Doppler and Near-infrared Spectroscopy Investigation

Advances in Experimental Medicine and Biology. 2008  |  Pubmed ID: 18290350

Recent advances in near-infrared spectroscopy (NIRS) allow measurements of absolute tissue oxygen saturation (TOI) using spatially resolved spectroscopy (SRS), while enabling better depth sensitivity. However concerns remain regarding the relative contribution of the extracranial circulation to the cerebral NIRS TOI signal. In this study we investigated this during a period of selective rise in cerebral blood flow (CBF) produced by the administration of acetazolamide (ACZ) in 10 healthy volunteers. A two channel spectrometer (NIRO 300, Hamamatsu Photonics KK) was used to measure absolute cerebral TOI over the frontal cortex using the SRS technique using an optode spacing of 5 cm and 1.5 cm for channel 1 and 2 respectively. After ACZ administration we were able to observe a significant increase in the velocity of middle cerebral artery (V(mca), measured with the transcranial Doppler (TCD)) which was accompanied by an increase in TOI as monitored by the NIRO 300 with an optode spacing of 5 cm but not with an optode spacing of 1.5 cm. Furthermore a direct relationship was seen between the V(mca) and the TOI measured at 5 cm optode spacing. This work suggests that using this commercial NIRS instrument with an optode spacing of 5 cm one is able to detect the intracranial changes.

Measurement of Frontal Lobe Functional Activation and Related Systemic Effects: a Near-infrared Spectroscopy Investigation

Advances in Experimental Medicine and Biology. 2008  |  Pubmed ID: 18290351

Near-infrared spectroscopy (NIRS) has been used to measure changes in cerebral oxy- and deoxy- haemoglobin (delta[HbO2], delta[HHb]) in response to functional activation. It has been previously reported that during functional activation of the motor cortex heart rate increases. The aim of this study was to investigate systemic changes during functional activation of the frontal cortex. The responses to anagram presentations with varying difficulty (4-Letters and 7-Letters) over a 6 minute period were recorded. A Hamamatsu NIRO 200 NIRS system recorded delta[HbO2] and delta[HHb] using the modified Beer Lambert law (MBL) and tissue oxygenation index (TOI) employing spatial resolved spectroscopy (SRS) over the left and right frontal hemisphere. Mean blood pressure (MBP) and heart rate (HR) were measured continuously. Nine young healthy volunteers (mean age 23) were included in the analysis. Significant task related changes were observed in both the NIRS and systemic signals during the anagram solving with increases in [HbO2] and [HHb] accompanied by changes in MBP and HR. The [HbO2] and [HHb] signals measured over the frontal region were found to have a varying association with the MBP signal across different volunteers. The effect of these systemic changes on measured NIRS signals must be considered

Increase in Cerebral Aerobic Metabolism by Normobaric Hyperoxia After Traumatic Brain Injury

Journal of Neurosurgery. Sep, 2008  |  Pubmed ID: 18759572

Traumatic brain injury (TBI) is associated with depressed aerobic metabolism and mitochondrial dysfunction. Normobaric hyperoxia (NBH) has been suggested as a treatment for TBI, but studies in humans have produced equivocal results. In this study the authors used brain tissue O(2) tension measurement, cerebral microdialysis, and near-infrared spectroscopy to study the effects of NBH after TBI. They investigated the effects on cellular and mitochondrial redox states measured by the brain tissue lactate/pyruvate ratio (LPR) and the change in oxidized cytochrome c oxidase (CCO) concentration, respectively.

Estimating a Modified Grubb's Exponent in Healthy Human Brains with Near Infrared Spectroscopy and Transcranial Doppler

Physiological Measurement. Jan, 2009  |  Pubmed ID: 19039165

The relationship between cerebral blood volume (CBV) and flow (CBF) has been widely studied. One of the most significant early studies was by Grubb et al (1974 Stroke 5 630-9), who conducted hypercapnia studies in primates with positron emission tomography (PET) and empirically found CBV = 0.8 CBF(0.38). The exponent used here has since been known as the Grubb's exponent. In this paper, we define a similar exponent known as the modified Grubb's exponent, G', which is based on CBV and cerebral blood flow velocity (CBFV) estimated by near infrared spectroscopy (NIRS) and transcranial Doppler respectively, i.e. G' = log(CBV/CBV(0))/log(CBFV/CBFV(0)), where CBV(0) and CBFV(0) are baseline values. The aim of this study was to estimate the nominal value of the modified Grubb's exponent in healthy human brains. We conducted hypercapnia and hypocapnia studies on 14 healthy adult subjects. The correlation coefficient between log(CBV/CBV(0)) and log(CBFV/CBFV(0)) is 0.71 (p < 0.0001). We found a modified Grubb's exponent of 0.13 (the 95% confidence bounds are 0.10 and 0.17) which is expectedly lower than the conventional Grubb's exponents estimated by other techniques. The modified Grubb's exponent is a simple measure to quantify the hemodynamics between local CBV and global CBFV in the brain and as such may provide insight on brain physiology. Both NIRS and transcranial Doppler techniques are non-invasive and portable, facilitating future studies in other population groups such as brain-injured patients.

False Positives in Functional Near-infrared Topography

Advances in Experimental Medicine and Biology. 2009  |  Pubmed ID: 19227487

Functional cranial near-infrared spectroscopy (NIRS) has been widely used to investigate the haemodynamic changes which occur in response to functional activation. The technique exploits the different absorption spectra of oxy- and deoxy-haemoglobin ([HbO2] [HHb]) in the near-infrared region to measure the changes in oxygenation and haemodynamics in the cortical tissue. The aim of this study was to use an optical topography system to produce topographic maps of the haemodynamic response of both frontal cortex (FC) and motor cortex (MC) during anagram solving while simultaneously monitoring the systemic physiology (mean blood pressure, heart rate, scalp flux). A total of 22 young healthy adults were studied. The activation paradigm comprised of 4-, 6- and 8- letter anagrams. 12 channels of the optical topography system were positioned over the FC and 12 channels over the MC. During the task 12 subjects demonstrated a significant change in at least one systemic variable (p < or = 0.05). Statistical analysis of task-related changes in [HbO2] and [HHb], based on a Student's t-test was insufficient to distinguish between cortical haemodynamic activation and systemic interference. This lead to false positive haemodynamic maps of activation. It is therefore necessary to use statistical testing that incorporates the systemic changes that occur during brain activation.

Relationship Between Brain Tissue Haemodynamics, Oxygenation and Metabolism in the Healthy Human Adult Brain During Hyperoxia and Hypercapnea

Advances in Experimental Medicine and Biology. 2009  |  Pubmed ID: 19227488

This study investigates the relationship between changes in brain tissue haemodynamics, oxygenation and oxidised cytochrome-c-oxidase ([oxCCO]) in the adult brain during hyperoxia and hypercapnea. 10 healthy volunteers were studied. We measured the mean blood flow velocity of the right middle cerebral artery (Vmca) with transcranial Doppler (TCD) and changes in concentrations of total haemoglobin ([HbT]=[HbO2]+[HHb]), haemoglobin difference ([Hbdiff]=[HbO2]-[HHb]) and [oxCCO] with broadband near-infrared spectroscopy (NIRS). We also measured the absolute tissue oxygenation index (TOI) using NIR spatially resolved spectroscopy. During hyperoxia there was an increase in TOI (2.33 +/- 0.29%), [Hbdiff] (4.57 +/- 1.27 microM) and in the oxidation of [oxCCO] (0.09 +/- 0.12 microM); but a reduction in Vmca (5.85 +/- 4.85%) and HbT (1.29 +/- 0.91 microM). During hyperoxia there was a positive correlation between [oxCCO] and TOI and [Hbdiff] (r=0.83 and r=0.95) and a negative association between [oxCCO] and Vmca and [HbT] (r=-0.74 and r=-0.87). During hypercapnea there was an increase in TOI (2.76 +/- 2.16%), [Hbdiff] (7.36 +/- 2.64), [HbT] (2.61 +/- 2.7 microM), Vmca (14.92 +/- 17.5%) and in the oxidation of [oxCCO] (0.25 +/- 0.17 microM). Correlation analysis shows that there was association between [oxCCO] and TOI, [Hbdiff] and [HbT] (r=0.83, r=0.93 and r=0.82) but not with Vmca (r=0.33). We conclude that an increase in [oxCCO] was seen during both challenges and it was highly associated with brain tissue oxygenation.

The Effect on Cerebral Tissue Oxygenation Index of Changes in the Concentrations of Inspired Oxygen and End-tidal Carbon Dioxide in Healthy Adult Volunteers

Anesthesia and Analgesia. Sep, 2009  |  Pubmed ID: 19690266

A variety of near-infrared spectroscopy devices can be used to make noninvasive measurements of cerebral tissue oxygen saturation (ScO2). The ScO2 measured by the NIRO 300 spectrometer (Hamamatsu Photonics, Japan) is called the cerebral tissue oxygenation index (TOI) and is an assessment of the balance between cerebral oxygen delivery and utilization. We designed this study to investigate the effect of systemic and intracranial physiological changes on TOI.

A Hybrid Multi-distance Phase and Broadband Spatially Resolved Spectrometer and Algorithm for Resolving Absolute Concentrations of Chromophores in the Near-infrared Light Spectrum

Advances in Experimental Medicine and Biology. 2010  |  Pubmed ID: 20204788

For resolving absolute concentration of tissue chromophores in the human adult brain with near-infrared spectroscopy it is necessary to calculate the light scattering and absorption, at multiple wavelengths with some depth resolution. To achieve this we propose an instrumentation configuration that combines multi-distance frequency and broadband spectrometers to quantify chromophores in turbid media by using a hybrid spatially resolved algorithm. Preliminary results in solid phantoms as well as liquid dynamic homogeneous and inhomogeneous phantoms and in-vivo muscle measurements showed encouraging results.

Functional Optical Topography Analysis Using Statistical Parametric Mapping (SPM) Methodology with and Without Physiological Confounds

Advances in Experimental Medicine and Biology. 2010  |  Pubmed ID: 20204798

Functional optical topography (OT) measures the changes in oxygenated and deoxygenated hemoglobin (HbO(2), HHb) across multiple brain sites which occur in response to neuronal activation of the cerebral cortex. However, identification of areas of cortical activation is a complex task due to intrinsic physiological noise and systemic interference and careful statistical analysis is therefore required. A total of 10 young healthy adults were studied. The activation paradigm comprised of anagrams followed by finger tapping. 12 channels of the OT system were positioned over the frontal cortex and 12 channels over the motor cortex while the systemic physiology (mean blood pressure (MBP), heart rate (HR), scalp flux) was simultaneously monitored. Analysis was done using the functional Optical Signal Analysis (fOSA) software and Statistical Parametric Mapping (SPM), where we utilized two approaches: (i) using only HbO(2) as a regressor in the general linear model (GLM) and (ii) using all of the explanatory variables (HbO(2), MBP, HR and scalp flux) as regressors. Group analysis using SPM showed significant correlation in a large number of OT channels between HbO(2) and systemic regressors; however no differences in activation areas were seen between the two approaches.

Modelling of Mitochondrial Oxygen Consumption and NIRS Detection of Cytochrome Oxidase Redox State

Advances in Experimental Medicine and Biology. 2010  |  Pubmed ID: 20204805

In recent years there has been widespread use of near infrared spectroscopy (NIRS) to monitor the brain. The signals of interest include changes in the levels of oxygenated and deoxygenated haemoglobin and tissue oxygen saturation. In addition to oxy- and deoxy-haemoglobin, the Cu(A) centre in cytochrome-c-oxidase (CCO) is a significant NIR absorber, giving rise to another signal termed the DeltaoxCCO signal. This signal has great potential as a marker of cellular oxygen metabolism, but is also the hardest to interpret. Here we use a recently constructed model to predict NIRS signal changes, and compare the model output to data from an in vivo hypoxia study in healthy adults. Our findings indicate strongly that the DeltaoxCCO signal contains useful information despite the noise, and has responses consistent with the known physiology.

Cerebral and Peripheral Tissue Oxygenation in Children Supported on ECMO for Cardio-respiratory Failure

Advances in Experimental Medicine and Biology. 2010  |  Pubmed ID: 20204828

Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for patients with cardio-respiratory failure. Establishing, maintaining and weaning from ECMO may increase the risk for intracranial injury. We used a dual channel near infrared system to monitor cerebral and peripheral tissue oxygenation in 3 venoarterial (VA) and 1 venovenous (VV) ECMO patients undergoing manipulations in the ECMO circuit flows. Spectral analysis was performed on the oxyhaemoglobin data collected from these patients with the aim of comparing oscillations at range of frequencies appearing in the two measurement sites.

Regional Cerebral Oxygenation Measured by Multichannel Near-infrared Spectroscopy (optical Topography) in an Infant Supported on Venoarterial Extracorporeal Membrane Oxygenation

The Journal of Thoracic and Cardiovascular Surgery. May, 2011  |  Pubmed ID: 21334016

Analysis of the Changes in the Oxidation of Brain Tissue Cytochrome-c-oxidase in Traumatic Brain Injury Patients During Hypercapnoea: a Broadband NIRS Study

Advances in Experimental Medicine and Biology. 2011  |  Pubmed ID: 21445763

Using broadband near-infrared spectroscopy (NIRS) and cerebral microdialysis (MD),we investigated cerebral cellular metabolism and mitochondrial redox states, following hypercapnoea in 6 patients with traumatic brain injury (TBI). In all patients hypercapnoea increased intracranial pressure and cerebral blood flow velocity measured with transcranial Doppler. Despite the likely increase in cerebral oxygen delivery, we did not see an increase in the oxidation status of cytochrome-c-oxidase [oxCCO] in every patient. Analysis of the NIRS data demonstrated two patterns of the changes; Group A (n = 4) showed an increase in [oxCCO] of 0.34(± 0.34)µM and Group B (n = 2) a decrease of 0.40(± 0.41)µM. Although no obvious association was seen between the Δ[oxCCO] and the MD, measured changes in lactate and pyruvate concentrations. Further work using model informed data interpretation may be helpful in understanding the multimodal signals acquired in this heterogeneous patient group.

Effects of Assuming Constant Optical Scattering on Haemoglobin Concentration Measurements Using NIRS During a Valsalva Manoeuvre

Advances in Experimental Medicine and Biology. 2011  |  Pubmed ID: 21445764

Resolving for changes in concentration of tissue chromophores in the human adult brain with near-infrared spectroscopy has generally been based on the assumption that optical scattering and pathlength remain constant. We have used a novel hybrid optical spectrometer that combines multi-distance frequency and broadband systems to investigate the changes in scattering and pathlength during a Valsalva manoeuvre in 8 adult volunteers. Results show a significant increase in the reduced scattering coefficient of 17% at 790nm and 850nm in 4 volunteers during the peak of the Valsalva. However, these scattering changes do not appear to significantly affect the differential pathlength factor and the tissue haemoglobin concentration measurements.

Quantification of Systemic Interference in Optical Topography Data During Frontal Lobe and Motor Cortex Activation: an Independent Component Analysis

Advances in Experimental Medicine and Biology. 2011  |  Pubmed ID: 21445768

Functional near-infrared optical topography (OT) is used to non-invasively measure the changes in oxygenated and deoxygenated haemoglobin (Δ[HbO2], Δ[HHb]) and hence investigate the brain haemodynamic changes, which occur in response to functional activation at specific regions of the cerebral cortex. However, when analysing functional OT data the task-related systemic changes should be taken into account.Here we used an independent component analysis (ICA) method on the OT [HbO2] signal, to determine the task-related independent components and then compared them with the systemic measurements (blood pressure, heart rate, scalp blood flow) to assess whether the components are due to systemic noise or neuronal activation. This analysis can therefore extract the true OT haemodynamic neuronal response and hence discriminate between regional activated cortical areas and global haemodynamic changes.

Experimental Validation of Alternating Transillumination for Imaging Intramural Wave Propagation

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference. 2011  |  Pubmed ID: 22254647

Current techniques to map intramural activation patterns in ex vivo cardiac tissue have limited spatial resolution. Here, we report on the experimental validation of a novel optical technique that was recently proposed to resolve the size and depth of intramural wave fronts using alternating transillumination (AT). AT was achieved by simultaneously mapping the epi- and endocardial surfaces with two synchronized CCD cameras and rapidly alternating LED illumination between both surfaces. Optical phantoms were made based on tissue optical properties measured using a hybrid optical spectrometer. Spherical fluorescent sources (Scarlet microspheres, Invitrogen, UK) of varying sizes were embedded at known depths in the phantoms. Coronary-perfused procine left ventricular slab preparations were stained with DI-4-ANBDQBS (n = 3) and paced at known intramural depths. In phantoms we were able to reliably estimate the depth of the center of fluorescent sources (9.6 ± 5.4% error), as well as their transmural extent (15.7 ± 11.5% error). In ventricular slabs we were able to localize the sites of origin of intramural excitation waves with a precision of ± 1.6 mm. Transmural conduction velocities were, for the first time, measured optically from the surfaces and found to be 21.0 ± 12.4 cm/s. In conclusion, alternating transillumination is a promising technique for reliable reconstruction of depth and expansion rate of intramural activation wave fronts in cardiac tissue.

Optical Topography to Measure Variations in Regional Cerebral Oxygenation in an Infant Supported on Veno-arterial Extra-corporeal Membrane Oxygenation

Advances in Experimental Medicine and Biology. 2012  |  Pubmed ID: 22259084

Use of a Hybrid Optical Spectrometer for the Measurement of Changes in Oxidized Cytochrome C Oxidase Concentration and Tissue Scattering During Functional Activation

Advances in Experimental Medicine and Biology. 2012  |  Pubmed ID: 22259091

Development of a Model to Aid NIRS Data Interpretation: Results from a Hypercapnia Study in Healthy Adults

Advances in Experimental Medicine and Biology. 2012  |  Pubmed ID: 22259116

Computational Modelling of the Piglet Brain to Simulate Near-infrared Spectroscopy and Magnetic Resonance Spectroscopy Data Collected During Oxygen Deprivation

Journal of the Royal Society, Interface / the Royal Society. Jul, 2012  |  Pubmed ID: 22279158

We describe a computational model to simulate measurements from near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS) in the piglet brain. Piglets are often subjected to anoxic, hypoxic and ischaemic insults, as experimental models for human neonates. The model aims to help interpret measurements and increase understanding of physiological processes occurring during such insults. It is an extension of a previous model of circulation and mitochondrial metabolism. This was developed to predict NIRS measurements in the brains of healthy adults i.e. concentration changes of oxyhaemoglobin and deoxyhaemoglobin and redox state changes of cytochrome c oxidase (CCO). We altered and enhanced the model to apply to the anaesthetized piglet brain. It now includes metabolites measured by (31)P-MRS, namely phosphocreatine, inorganic phosphate and adenosine triphosphate (ATP). It also includes simple descriptions of glycolysis, lactate dynamics and the tricarboxylic acid (TCA) cycle. The model is described, and its simulations compared with existing measurements from piglets during anoxia. The NIRS and MRS measurements are predicted well, although this requires a reduction in blood pressure autoregulation. Predictions of the cerebral metabolic rate of oxygen consumption (CMRO(2)) and lactate concentration, which were not measured, are given. Finally, the model is used to investigate hypotheses regarding changes in CCO redox state during anoxia.

The Physiological Origin of Task-evoked Systemic Artefacts in Functional Near Infrared Spectroscopy

NeuroImage. May, 2012  |  Pubmed ID: 22426347

A major methodological challenge of functional near-infrared spectroscopy (fNIRS) is its high sensitivity to haemodynamic fluctuations in the scalp. Superficial fluctuations contribute on the one hand to the physiological noise of fNIRS, impairing the signal-to-noise ratio, and may on the other hand be erroneously attributed to cerebral changes, leading to false positives in fNIRS experiments. Here we explore the localisation, time course and physiological origin of task-evoked superficial signals in fNIRS and present a method to separate them from cortical signals. We used complementary fNIRS, fMRI, MR-angiography and peripheral physiological measurements (blood pressure, heart rate, skin conductance and skin blood flow) to study activation in the frontal lobe during a continuous performance task. The General Linear Model (GLM) was applied to analyse the fNIRS data, which included an additional predictor to account for systemic changes in the skin. We found that skin blood volume strongly depends on the cognitive state and that sources of task-evoked systemic signals in fNIRS are co-localized with veins draining the scalp. Task-evoked superficial artefacts were mainly observed in concentration changes of oxygenated haemoglobin and could be effectively separated from cerebral signals by GLM analysis. Based on temporal correlation of fNIRS and fMRI signals with peripheral physiological measurements we conclude that the physiological origin of the systemic artefact is a task-evoked sympathetic arterial vasoconstriction followed by a decrease in venous volume. Since changes in sympathetic outflow accompany almost any cognitive and emotional process, we expect scalp vessel artefacts to be present in a wide range of fNIRS settings used in neurocognitive research. Therefore a careful separation of fNIRS signals originating from activated brain and from scalp is a necessary precondition for unbiased fNIRS brain activation maps.

Modelling Noninvasively Measured Cerebral Signals During a Hypoxemia Challenge: Steps Towards Individualised Modelling

PloS One. 2012  |  Pubmed ID: 22679497

Noninvasive approaches to measuring cerebral circulation and metabolism are crucial to furthering our understanding of brain function. These approaches also have considerable potential for clinical use "at the bedside". However, a highly nontrivial task and precondition if such methods are to be used routinely is the robust physiological interpretation of the data. In this paper, we explore the ability of a previously developed model of brain circulation and metabolism to explain and predict quantitatively the responses of physiological signals. The five signals all noninvasively-measured during hypoxemia in healthy volunteers include four signals measured using near-infrared spectroscopy along with middle cerebral artery blood flow measured using transcranial Doppler flowmetry. We show that optimising the model using partial data from an individual can increase its predictive power thus aiding the interpretation of NIRS signals in individuals. At the same time such optimisation can also help refine model parametrisation and provide confidence intervals on model parameters. Discrepancies between model and data which persist despite model optimisation are used to flag up important questions concerning the underlying physiology, and the reliability and physiological meaning of the signals.

Multichannel Near Infrared Spectroscopy Indicates Regional Variations in Cerebral Autoregulation in Infants Supported on Extracorporeal Membrane Oxygenation

Journal of Biomedical Optics. Jun, 2012  |  Pubmed ID: 22734786

Assessing noninvasively cerebral autoregulation, the protective mechanism of the brain to maintain constant cerebral blood flow despite changes in blood pressure, is challenging. Infants on life support system (ECMO) for cardiorespiratory failure are at risk of cerebral autoregulation impairment and consequent neurological problems. We measured oxyhaemoglobin concentration (HbO(2)) by multichannel (12 channels) near-infrared spectroscopy (NIRS) in six infants during sequential changes in ECMO flow. Wavelet cross-correlation (WCC) between mean arterial pressure (MAP) and HbO(2) was used to construct a time-frequency representation of the concordance between the two signals to assess the nonstationary aspect of cerebral autoregulation and investigate regional variations. Group data showed that WCC increases with decreasing ECMO flow indicating higher concordance between MAP and HbO(2) and demonstrating loss of cerebral autoregulation at low ECMO flows. Statistically significant differences in WCC were observed between channels placed on the right and left scalp with channels on the right exhibiting higher values of WCC suggesting that the right hemisphere was more susceptible to disruption of cerebral autoregulation. Multichannel NIRS in conjunction with wavelet analysis methods can be used to assess regional variations in dynamic cerebral autoregulation with important clinical application in the management of critically ill children on life support systems.

Systematic Investigation of Changes in Oxidized Cerebral Cytochrome C Oxidase Concentration During Frontal Lobe Activation in Healthy Adults

Biomedical Optics Express. Oct, 2012  |  Pubmed ID: 23082295

Using transcranial near-infrared spectroscopy (NIRS) to measure changes in the redox state of cerebral cytochrome c oxidase (Δ[oxCCO]) during functional activation in healthy adults is hampered by instrumentation and algorithm issues. This study reports the Δ[oxCCO] response measured in such a setting and investigates possible confounders of this measurement. Continuous frontal lobe NIRS measurements were collected from 11 healthy volunteers during a 6-minute anagram-solving task, using a hybrid optical spectrometer (pHOS) that combines multi-distance frequency and broadband components. Only data sets showing a hemodynamic response consistent with functional activation were interrogated for a Δ[oxCCO] response. Simultaneous systemic monitoring data were also available. Possible influences on the Δ[oxCCO] response were systematically investigated and there was no effect of: 1) wavelength range chosen for fitting the measured attenuation spectra; 2) constant or measured, with the pHOS in real-time, differential pathlength factor; 3) systemic hemodynamic changes during functional activation; 4) changes in optical scattering during functional activation. The Δ[oxCCO] response measured in the presence of functional activation was heterogeneous, with the majority of subjects showing significant increase in oxidation, but others having a decrease. We conclude that the heterogeneity in the Δ[oxCCO] response is physiological and not induced by confounding factors in the measurements.

Canonical Correlation Analysis in the Study of Cerebral and Peripheral Haemodynamics Interrelations with Systemic Variables in Neonates Supported on ECMO

Advances in Experimental Medicine and Biology. 2013  |  Pubmed ID: 22879010

Neonates supported on extracorporeal membrane oxygenation (ECMO) are at high risk of brain injury due to haemodynamic instability. In order to monitor cerebral and peripheral (muscle) haemodynamic and oxygenation changes in this population we used a dual-channel near-infrared spectroscopy (NIRS) system. In addition, to assess interrelations between NIRS and systemic variables, collected simultaneously, canonical correlation analysis (CCA) was employed. CCA can quantify the relationship between a set of variables and assess levels of dependency. In four out of five patients, systemic variables were found to be less inter-related with cerebral rather than peripheral NIRS measurements. Moreover, during ECMO flow manipulations, we found that the interrelation between the systemic and the NIRS cerebral/peripheral variables changed. The CCA method presented here can be used to assess differences between NIRS cerebral and NIRS peripheral responses due to systemic variations which may be indicative of physiological differences in the mechanisms that regulate oxygenation and/or haemodynamics of the brain and the muscle.

Normobaric Hyperoxia Does Not Change Optical Scattering or Pathlength but Does Increase Oxidised Cytochrome C Oxidase Concentration in Patients with Brain Injury

Advances in Experimental Medicine and Biology. 2013  |  Pubmed ID: 22879016

We report the use of a novel hybrid near-infrared spectrometer for the measurement of optical scattering, pathlength and chromophore concentration in critically ill patients with brain injury. Ten mechanically ventilated patients with acute brain injury were studied. In addition to standard neurointensive care monitoring, middle cerebral artery flow velocity, brain lactate-pyruvate ratio (LPR) and brain tissue oxygen tension were monitored. The patients were subjected to graded normobaric hyperoxia (NBH), with the inspired fraction of oxygen increased from baseline to 60% then 100%. NBH induced significant changes in the concentrations of oxyhaemoglobin, deoxyhaemoglobin and oxidised-reduced cytochrome c oxidase; these were accompanied by a corresponding reduction in brain LPR and increase in brain tissue oxygen tension. No significant change in optical scattering or pathlength was observed. These results suggest that the measurement of chromophore concentration in the injured brain is not confounded by changes in optical scattering or pathlength and that NBH induces an increase in cerebral aerobic metabolism.

Modelling Cerebrovascular Reactivity: a Novel Near-infrared Biomarker of Cerebral Autoregulation?

Advances in Experimental Medicine and Biology. 2013  |  Pubmed ID: 22879019

Understanding changes in cerebral oxygenation, haemodynamics and metabolism holds the key to individualised, optimised therapy after acute brain injury. Near-infrared spectroscopy (NIRS) offers the potential for non-invasive, continuous bedside measurement of surrogates for these processes. Interest has grown in applying this technique to interpret cerebrovascular pressure reactivity (CVPR), a surrogate of the brain's ability to autoregulate blood flow. We describe a physiological model-based approach to NIRS interpretation which predicts autoregulatory efficiency from a model parameter k_aut. Data from three critically brain-injured patients exhibiting a change in CVPR were investigated. An optimal value for k_aut was determined to minimise the difference between measured and simulated outputs. Optimal values for k_aut appropriately tracked changes in CVPR under most circumstances. Further development of this technique could be used to track CVPR providing targets for individualised management of patients with altered vascular reactivity, minimising secondary neurological insults.

Oscillations in Cerebral Haemodynamics in Patients with Falciparum Malaria

Advances in Experimental Medicine and Biology. 2013  |  Pubmed ID: 22879021

Spontaneous oscillations in cerebral haemodynamics studied with near-infrared spectroscopy (NIRS), become impaired in several pathological conditions. We assessed the spectral characteristics of these oscillations in 20 patients with falciparum malaria admitted to Ispat General Hospital, Rourkela, India. Monitoring included continuous frontal lobe NIRS recordings within 24 h of admission (Day 0), together with single measurements of a number of clinical and chemical markers recorded on admission. Seven patients returned for follow-up measurements on recovery (FU). A 2,048 sampling-point segment of oxygenated haemoglobin concentration ([ΔHbO(2)]) data was subjected to Fourier analysis per patient, and power spectral density was derived over the very low frequency (VLF: 0.02-0.04 Hz), low frequency (LF: 0.04-0.15 Hz) and high frequency (HF: 0.15-0.4 Hz) bands. At Day 0, VLF spectral power was 21.1 ± 16.4, LF power 7.2 ± 4.6 and HF power 2.6 ± 5.0, with VLF power being statistically significantly higher than LF and HF (P < 0.005). VLF power tended to decrease in the severely ill patients and correlated negatively with heart rate (r = 0.57, P < 0.01), while LF power correlated positively with aural body temperature (r = 0.49, P < 0.05). In all but one of the patients who returned for FU measurements, VLF power increased after recovery. This may be related to autonomic dysfunction in severe malaria, a topic of little research to date. The present study demonstrated that application of NIRS in a resource-poor setting is feasible and has potential as a research tool.

Wavelet Cross-correlation to Investigate Regional Variations in Cerebral Oxygenation in Infants Supported on Extracorporeal Membrane Oxygenation

Advances in Experimental Medicine and Biology. 2013  |  Pubmed ID: 22879034

Extracorporeal membrane oxygenation can potentially affect cerebral blood flow dynamics and consequently influence cerebral autoregulation. We applied wavelet cross-correlation (WCC) between multichannel cerebral oxyhemoglobin concentration (HbO(2)) and mean arterial pressure (MAP), to assess regional variations in cerebral autoregulation. Six infants on veno-arterial (VA) ECMO were studied during sequential changes in the ECMO flows. WCC between MAP and HbO(2) for each flow period and each channel was calculated within three different frequency (wavelet scale) bands centered around 0.1, 0.16, and 0.3 Hz chosen to represent low frequency oscillations, ventilation, and respiration rates, respectively. The group data showed a relationship between maximum WCC and ECMO flow. During changes in ECMO flow, statistically significant differences in maximum WCC were found between right and left hemispheres. WCC between HbO(2) and MAP provides a useful method to investigate the dynamics of cerebral autoregulation during ECMO. Manipulations of ECMO flows are associated with regional changes in cerebral autoregulation which may potentially have an important bearing on clinical outcome.

Long-term Enhancement of Brain Function and Cognition Using Cognitive Training and Brain Stimulation

Current Biology : CB. Jun, 2013  |  Pubmed ID: 23684971

Noninvasive brain stimulation has shown considerable promise for enhancing cognitive functions by the long-term manipulation of neuroplasticity. However, the observation of such improvements has been focused at the behavioral level, and enhancements largely restricted to the performance of basic tasks. Here, we investigate whether transcranial random noise stimulation (TRNS) can improve learning and subsequent performance on complex arithmetic tasks. TRNS of the bilateral dorsolateral prefrontal cortex (DLPFC), a key area in arithmetic, was uniquely coupled with near-infrared spectroscopy (NIRS) to measure online hemodynamic responses within the prefrontal cortex. Five consecutive days of TRNS-accompanied cognitive training enhanced the speed of both calculation- and memory-recall-based arithmetic learning. These behavioral improvements were associated with defined hemodynamic responses consistent with more efficient neurovascular coupling within the left DLPFC. Testing 6 months after training revealed long-lasting behavioral and physiological modifications in the stimulated group relative to sham controls for trained and nontrained calculation material. These results demonstrate that, depending on the learning regime, TRNS can induce long-term enhancement of cognitive and brain functions. Such findings have significant implications for basic and translational neuroscience, highlighting TRNS as a viable approach to enhancing learning and high-level cognition by the long-term modulation of neuroplasticity.

Reduction of Cytochrome C Oxidase During Vasovagal Hypoxia-ischemia in Human Adult Brain: a Case Study

Advances in Experimental Medicine and Biology. 2013  |  Pubmed ID: 23852472

Near-infrared spectroscopy (NIRS)-derived measurement of oxidized cytochrome c oxidase concentration ([oxCCO]) has been used as an assessment of the adequacy of cerebral oxygen delivery. We report a case in which a reduction in conscious level was associated with a reduction in [oxCCO]. Hypoxaemia was induced in a 31-year-old, healthy male subject as part of an ongoing clinical study. Midway through the hypoxaemic challenge, the subject experienced an unexpected vasovagal event with bradycardia, hypotension and reduced cerebral blood flow (middle cerebral artery blood flow velocity decrease from 70 to 30 cm s(-1)) that induced a brief reduction in conscious level. An associated decrease in [oxCCO] was observed at 35 mm (-1.6 μM) but only minimal change (-0.1 μM) at 20-mm source-detector separation. A change in optical scattering was observed, but path length remained unchanged. This unexpected physiological event provides an unusual example of a severe reduction in cerebral oxygen delivery and is the first report correlating change in clinical status with changes in [oxCCO].

Investigation of Frontal Lobe Activation with FNIRS and Systemic Changes During Video Gaming

Advances in Experimental Medicine and Biology. 2013  |  Pubmed ID: 23852481

Frontal lobe activation caused by tasks such as videogames can be investigated using multichannel near-infrared spectroscopy (fNIRS), sometimes called optical topography. The aims of this study are to investigate the effects of video gaming (fighting and puzzle games) in the brain and the systemic physiology and to determine whether systemic responses during the gaming task are associated with the measurement of localised cerebral haemodynamic changes as measured by fNIRS. We used a continuous-wave 8-channel fNIRS system to measure the changes in concentration of oxy-haemoglobin (HbO2) and deoxy-haemoglobin (HHb) and changes in total haemoglobin (ΔtHb = ΔHbO2 + ΔHHb) over the frontal lobe in 30 healthy volunteers. The Portapres system was used to measure mean blood pressure (MBP) and heart rate (HR), and a laser Doppler was employed to measure the changes in scalp blood flow (or flux). Even though we observed significant changes in systemic variables during gaming, in particular in scalp flow, we also managed to see localised activation patterns over the frontal polar (FP1) region. However, in some channels over the frontal lobe, we also observed significant correlations between the HbO2 and systemic variables.

Modelling Blood Flow and Metabolism in the Piglet Brain During Hypoxia-ischaemia: Simulating PH Changes

Advances in Experimental Medicine and Biology. 2013  |  Pubmed ID: 23852512

We describe the extension of a computational model of blood flow and metabolism in the piglet brain to investigate changes in neonatal intracellular brain pH during hypoxia-ischemia (HI). The model is able to simulate near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS) measurements obtained from HI experiments conducted in piglets. We adopt a method of using (31)P-MRS data to estimate of intracellular pH and compare measured pH and oxygenation with their modelled counterparts. We show that both NIRS and MRS measurements are predicted well in the new version of the model.

Modelling Blood Flow and Metabolism in the Piglet Brain During Hypoxia-ischaemia: Simulating Brain Energetics

Advances in Experimental Medicine and Biology. 2013  |  Pubmed ID: 23852513

We have developed a computational model to simulate hypoxia-ischaemia (HI) in the neonatal piglet brain. It has been extended from a previous model by adding the simulation of carotid artery occlusion and including pH changes in the cytoplasm. Here, simulations from the model are compared with near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy (MRS) measurements from two piglets during HI and short-term recovery. One of these piglets showed incomplete recovery after HI, and this is modelled by considering some of the cells to be dead. This is consistent with the results from MRS and the redox state of cytochrome-c-oxidase as measured by NIRS. However, the simulations do not match the NIRS haemoglobin measurements. The model therefore predicts that further physiological changes must also be taking place if the hypothesis of dead cells is correct.

Dependence on NIRS Source-detector Spacing of Cytochrome C Oxidase Response to Hypoxia and Hypercapnia in the Adult Brain

Advances in Experimental Medicine and Biology. 2013  |  Pubmed ID: 23852515

Transcranial near-infrared spectroscopy (NIRS) provides an assessment of cerebral oxygen metabolism by monitoring concentration changes in oxidised cytochrome c oxidase Δ[oxCCO]. We investigated the response of Δ[oxCCO] to global changes in cerebral oxygen delivery at different source-detector separations in 16 healthy adults. Hypoxaemia was induced by delivery of a hypoxic inspired gas mix and hypercapnia by addition of 6 % CO2 to the inspired gases. A hybrid optical spectrometer was used to measure frontal cortex light absorption and scattering at discrete wavelengths and broadband light attenuation at 20, 25, 30 and 35 mm. Without optical scattering changes, a decrease in cerebral oxygen delivery, resulting from the reduction in arterial oxygen saturation during hypoxia, led to a decrease in Δ[oxCCO]. In contrast, Δ[oxCCO] increased when cerebral oxygen delivery increased due to increased cerebral blood flow during hypercapnia. In both cases the magnitude of the Δ[oxCCO] response increased from the detectors proximal (measuring superficial tissue layers) to the detectors distal (measuring deep tissue layers) to the broadband light source. We conclude that the Δ[oxCCO] response to hypoxia and hypercapnia appears to be dependent on penetration depth, possibly reflecting differences between the intra- and extracerebral tissue concentration of cytochrome c oxidase.

Identifying and Quantifying Main Components of Physiological Noise in Functional Near Infrared Spectroscopy on the Prefrontal Cortex

Frontiers in Human Neuroscience. 2013  |  Pubmed ID: 24399947

Functional Near-Infrared Spectroscopy (fNIRS) is a promising method to study functional organization of the prefrontal cortex. However, in order to realize the high potential of fNIRS, effective discrimination between physiological noise originating from forehead skin haemodynamic and cerebral signals is required. Main sources of physiological noise are global and local blood flow regulation processes on multiple time scales. The goal of the present study was to identify the main physiological noise contributions in fNIRS forehead signals and to develop a method for physiological de-noising of fNIRS data. To achieve this goal we combined concurrent time-domain fNIRS and peripheral physiology recordings with wavelet coherence analysis (WCA). Depth selectivity was achieved by analyzing moments of photon time-of-flight distributions provided by time-domain fNIRS. Simultaneously, mean arterial blood pressure (MAP), heart rate (HR), and skin blood flow (SBF) on the forehead were recorded. WCA was employed to quantify the impact of physiological processes on fNIRS signals separately for different time scales. We identified three main processes contributing to physiological noise in fNIRS signals on the forehead. The first process with the period of about 3 s is induced by respiration. The second process is highly correlated with time lagged MAP and HR fluctuations with a period of about 10 s often referred as Mayer waves. The third process is local regulation of the facial SBF time locked to the task-evoked fNIRS signals. All processes affect oxygenated haemoglobin concentration more strongly than that of deoxygenated haemoglobin. Based on these results we developed a set of physiological regressors, which were used for physiological de-noising of fNIRS signals. Our results demonstrate that proposed de-noising method can significantly improve the sensitivity of fNIRS to cerebral signals.

Cytochrome C Oxidase Response to Changes in Cerebral Oxygen Delivery in the Adult Brain Shows Higher Brain-specificity Than Haemoglobin

NeuroImage. Jan, 2014  |  Pubmed ID: 23707584

The redox state of cerebral mitochondrial cytochrome c oxidase monitored with near-infrared spectroscopy (Δ[oxCCO]) is a signal with strong potential as a non-invasive, bedside biomarker of cerebral metabolic status. We hypothesised that the higher mitochondrial density of brain compared to skin and skull would lead to evidence of brain-specificity of the Δ[oxCCO] signal when measured with a multi-distance near-infrared spectroscopy (NIRS) system. Measurements of Δ[oxCCO] as well as of concentration changes in oxygenated (Δ[HbO2]) and deoxygenated haemoglobin (Δ[HHb]) were taken at multiple source-detector distances during systemic hypoxia and hypocapnia (decrease in cerebral oxygen delivery), and hyperoxia and hypercapnia (increase in cerebral oxygen delivery) from 15 adult healthy volunteers. Increasing source-detector spacing is associated with increasing light penetration depth and thus higher sensitivity to cerebral changes. An increase in Δ[oxCCO] was observed during the challenges that increased cerebral oxygen delivery and the opposite was observed when cerebral oxygen delivery decreased. A consistent pattern of statistically significant increasing amplitude of the Δ[oxCCO] response with increasing light penetration depth was observed in all four challenges, a behaviour that was distinctly different from that of the haemoglobin chromophores, which did not show this statistically significant depth gradient. This depth-dependence of the Δ[oxCCO] signal corroborates the notion of higher concentrations of CCO being present in cerebral tissue compared to extracranial components and highlights the value of NIRS-derived Δ[oxCCO] as a brain-specific signal of cerebral metabolism, superior in this aspect to haemoglobin.

A Novel Non-amplification Assay for the Detection of Leishmania Spp. in Clinical Samples Using Gold Nanoparticles

Journal of Microbiological Methods. Jan, 2014  |  Pubmed ID: 24184015

Leishmaniosis is a zoonose caused by protozoans of the genus Leishmania. The need for accurate diagnostic investigation of cases of leishmaniosis has rendered today the use of molecular biology techniques broadly applicable. However, the reliable application of these methods requires highly-specialised personnel, dedicated equipment and space. The aim of this study was the design and construction of functionalized gold nanoparticles (AuNPs) that would be incorporated into an easily applicable DNA detection methodology for the identification of Leishmania spp. in clinical samples. AuNPs 20nm in diameter were conjugated with four oligonucleotide probes, targeting kinetoplastid minicircle DNA of Leishmania spp. In the absence of complimentary DNA, AuNPs-probes precipitate under acid environment causing a change of color from red to purple, which can be detected by visual observation. In the presence of target DNA the color of the solution remains red. The specific methodology was applied to positive and negative control samples and whole blood collected from dogs with suspected canine leishmaniosis. The method's minimum detection limit was defined to 11.5ng of target DNA per μl of sample. Repeatability and reproducibility were 100%. Relative sensitivity and specificity referenced to PCR were calculated to 92% and 100% regarding collectively control and clinical samples. The proposed approach can be considered an appealing diagnostic solution especially for screening purposes in enzootic areas, where detection of very small amounts of the targeted analyte is not top priority.

Investigation of Cerebral Autoregulation in the Newborn Piglet During Anaesthesia and Surgery

Advances in Experimental Medicine and Biology. 2014  |  Pubmed ID: 24729229

The relationship between cerebral autoregulation (CA) and the neurotoxic effects of anaesthesia with and without surgery is investigated. Newborn piglets were randomly assigned to receive either 6 h of anaesthesia (isoflurane) or the same with an additional hour of minor surgery. The effect of the spontaneous changes in mean arterial blood pressure (MABP) on the cerebral haemodynamics (oxy- and deoxy-haemoglobin, HbO2 and Hb) was measured using transverse broadband near-infrared spectroscopy (NIRS). A marker for impaired CA, concordance between MABP and intravascular oxygenation (HbD = HbO2 - Hb) in the ultra-low frequency domain (0.0018-0.0083 Hz), was assessed using coherence analysis. Presence of CA impairment was not significant but found to increase with surgical exacerbation. The impairment did not correlate with histological outcome (presence of cell death, apoptosis and microglial activation in the brain).

Development of a Near Infrared Multi-wavelength, Multi-channel, Time-resolved Spectrometer for Measuring Brain Tissue Haemodynamics and Metabolism

Advances in Experimental Medicine and Biology. 2014  |  Pubmed ID: 24729231

We present a novel time domain functional near infrared spectroscopy system using a supercontinuum laser allowing us to measure the coefficient of absorption and scattering of up to 16 multiplexed wavelengths in the near infrared region. This is a four detector system that generates up to 3 mW of light for each wavelength with a narrow 2-3 nm FWHM bandwidth between 650 and 890 nm; each measurement of 16 wavelengths per channel can be performed up to a rate of 1 Hz. We can therefore quantify absolute haemoglobin changes in tissue and are currently investigating which and how many wavelengths are needed to resolve additional chromophores in tissue, such as water and the oxidation state of cytochrome-c-oxidase.

Simulating NIRS and MRS Measurements During Cerebral Hypoxia-ischaemia in Piglets Using a Computational Model

Advances in Experimental Medicine and Biology. 2014  |  Pubmed ID: 24729232

We present a group analysis of the changes in cerebral haemodynamics, and the oxidation state of cytochrome-c-oxidase measured using broadband near-infrared spectroscopy (NIRS) and intracellular pH measured by phosphorous ((31)P) magnetic resonance spectroscopy (MRS) during and after cerebral hypoxia-ischaemia (HI) in 15 piglets. We use a previously published computational model of cerebral metabolism in the piglet [1] to integrate these measurements and simulate HI. We successfully simulate changes in cellular metabolism including shifts in intracellular pH observed in the piglet brain during HI. In this process, we optimise physiological parameters in the model identified through sensitivity analysis (such as the rate of glucose metabolism and intracellular lactate concentration), to fit simulated and measured data. The model fits the data reasonably and suggests a 20 % drop in glucose consumption, a ~65 % increase in lactate concentration and ~35 % drop in the cerebral metabolic rate of oxygen (CMRO₂) during HI.

Analysis of Slow Wave Oscillations in Cerebral Haemodynamics and Metabolism Following Subarachnoid Haemorrhage

Advances in Experimental Medicine and Biology. 2014  |  Pubmed ID: 24729233

Aneurysmal subarachnoid haemorrhage (SAH) causes the greatest loss of productive life years of any form of stroke. Emerging concepts of pathophysiology highlight early abnormalities of microvascular function, including impaired autoregulation of cerebral blood flow and flow-metabolism coupling, as key causes of cerebral ischaemia and poor outcome. Near infrared spectroscopy (NIRS) is a non-invasive optical technique which may help identify cerebral microvascular dysfunction. The aim of this research is to investigate the status of flow-metabolism coupling by examining phase relationships between NIRS-derived concentrations of oxy-haemoglobin ([HbO₂]), deoxy-haemoglobin ([HHb]) and cytochrome c oxidase oxidation ([oxCCO]). Eight sedated ventilated patients with SAH were investigated. A combined NIRS broadband and frequency domain spectroscopy system was used to measure [HbO₂], [HHb] and [oxCCO] alongside other multimodal neuromonitoring. Wavelet analysis of phase relationships revealed antiphase [HbO₂]-[oxCCO] and in-phase [HbO₂]-[HHb] oscillations between 0.1Hz-0.01Hz consistent with compromised flow-metabolism coupling. NIRS derived variables might offer unique insights into microvascular and metabolic dysfunction following SAH, and in the future identify therapeutic windows or targets.

Separation of Superficial and Cerebral Hemodynamics Using a Single Distance Time-domain NIRS Measurement

Biomedical Optics Express. May, 2014  |  Pubmed ID: 24877009

In functional near-infrared spectroscopy (fNIRS) superficial hemodynamics can mask optical signals related to brain activity. We present a method to separate superficial and cerebral absorption changes based on the analysis of changes in moments of time-of-flight distributions and a two-layered model. The related sensitivity factors were calculated from individual optical properties. The method was validated on a two-layer liquid phantom. Absorption changes in the lower layer were retrieved with an accuracy better than 20%. The method was successfully applied to in vivo data and compared to the reconstruction of homogeneous absorption changes.

Dual Role of Cerebral Blood Flow in Regional Brain Temperature Control in the Healthy Newborn Infant

International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience. Oct, 2014  |  Pubmed ID: 24907512

Small shifts in brain temperature after hypoxia-ischaemia affect cell viability. The main determinants of brain temperature are cerebral metabolism, which contributes to local heat production, and brain perfusion, which removes heat. However, few studies have addressed the effect of cerebral metabolism and perfusion on regional brain temperature in human neonates because of the lack of non-invasive cot-side monitors. This study aimed (i) to determine non-invasive monitoring tools of cerebral metabolism and perfusion by combining near-infrared spectroscopy and echocardiography, and (ii) to investigate the dependence of brain temperature on cerebral metabolism and perfusion in unsedated newborn infants. Thirty-two healthy newborn infants were recruited. They were studied with cerebral near-infrared spectroscopy, echocardiography, and a zero-heat flux tissue thermometer. A surrogate of cerebral blood flow (CBF) was measured using superior vena cava flow adjusted for cerebral volume (rSVC flow). The tissue oxygenation index, fractional oxygen extraction (FOE), and the cerebral metabolic rate of oxygen relative to rSVC flow (CMRO₂ index) were also estimated. A greater rSVC flow was positively associated with higher brain temperatures, particularly for superficial structures. The CMRO₂ index and rSVC flow were positively coupled. However, brain temperature was independent of FOE and the CMRO₂ index. A cooler ambient temperature was associated with a greater temperature gradient between the scalp surface and the body core. Cerebral oxygen metabolism and perfusion were monitored in newborn infants without using tracers. In these healthy newborn infants, cerebral perfusion and ambient temperature were significant independent variables of brain temperature. CBF has primarily been associated with heat removal from the brain. However, our results suggest that CBF is likely to deliver heat specifically to the superficial brain. Further studies are required to assess the effect of cerebral metabolism and perfusion on regional brain temperature in low-cardiac output conditions, fever, and with therapeutic hypothermia.

A New Broadband Near-infrared Spectroscopy System for In-vivo Measurements of Cerebral Cytochrome-c-oxidase Changes in Neonatal Brain Injury

Biomedical Optics Express. Oct, 2014  |  Pubmed ID: 25360364

We present a novel lens-based broadband near-infrared spectroscopy system to simultaneously measure cerebral changes in tissue oxygenation and haemodynamics via estimation of the changes in haemoglobin concentration; in addition to oxygen utilization via the measurement of the oxidation state of cytochrome-c-oxidase (CCO). We demonstrate the use of the system in a cohort of 6 newborn infants with neonatal encephalopathy in the Neonatal Intensive Care Unit for continuous measurement periods of up to 5 days. NIRS data was collected from above the frontal lobe on the left and right hemispheres simultaneously with systemic data to allow multimodal data analysis. This allowed us to study the NIRS variables in response to global pathophysiological events and we focused our analysis to spontaneous oxygen desaturations. We identified changes from the NIRS variables during 236 oxygen desaturations from over 212 hours of data with a change from the baseline to nadir of -12 ± 3%. There was a consistent negative change in the Δ[HbD] (= oxygenated - deoxygenated haemoglobin) and Δ[oxCCO] measurements, mean decreases were 3.0 ± 1.7μM and 0.22 ± 0.11μM, and a positive change in the Δ[HbT] (= oxygenated + deoxygenated haemoglobin) measurements across all subjects, mean increase was 0.85 ± 0.58μM. We have shown with a feasibility study that the relationship between haemoglobin oxygenation changes and CCO oxidation changes during these desaturation events was significantly associated with a magnetic resonance spectroscopy (MRS)-measured biomarker of injury severity (r = 0.91, p<0.01).

Spatial Sensitivity and Penetration Depth of Three Cerebral Oxygenation Monitors

Biomedical Optics Express. Sep, 2014  |  Pubmed ID: 25401006

The spatial sensitivities of NIRO-100, ISS Oximeter and TRS-20 cerebral oxygenation monitors are mapped using the local perturbation method to inform on their penetration depths and susceptibilities to superficial contaminations. The results show that TRS-20 has the deepest mean penetration depth and is less sensitive than the other monitors to a localized absorption change in the superficial layer. However, an integration time of more than five seconds is required by the TRS-20 to achieve an acceptable level of signal-to-noise ratio, which is the poorest amongst the monitors. With the exception of NIRO-100 continuous wave method, the monitors are not significantly responsive to layer-wide absorption change that occurs in the superficial layer.

Optimal Wavelength Combinations for Near-infrared Spectroscopic Monitoring of Changes in Brain Tissue Hemoglobin and Cytochrome C Oxidase Concentrations

Biomedical Optics Express. Mar, 2015  |  Pubmed ID: 25798316

We analyze broadband near-infrared spectroscopic measurements obtained from newborn piglets subjected to hypoxia-ischemia and we aim to identify optimal wavelength combinations for monitoring cerebral tissue chromophores. We implement an optimization routine based on the genetic algorithm to perform a heuristic search for discrete wavelength combinations that can provide accurate concentration information when benchmarked against the gold standard of 121 wavelengths. The results indicate that it is possible to significantly reduce the number of measurement wavelengths used in conjunction with spectroscopic algorithms and still achieve a high performance in estimating changes in concentrations of oxyhemoglobin, deoxyhemoglobin, and oxidized cytochrome c oxidase. While the use of a 3-wavelength combination leads to mean recovery errors of up to 10%, these errors drop to less than 4% with 4 or 5 wavelengths and to even less than 2% with 8 wavelengths.

BrainSignals Revisited: Simplifying a Computational Model of Cerebral Physiology

PloS One. 2015  |  Pubmed ID: 25961297

Multimodal monitoring of brain state is important both for the investigation of healthy cerebral physiology and to inform clinical decision making in conditions of injury and disease. Near-infrared spectroscopy is an instrument modality that allows non-invasive measurement of several physiological variables of clinical interest, notably haemoglobin oxygenation and the redox state of the metabolic enzyme cytochrome c oxidase. Interpreting such measurements requires the integration of multiple signals from different sources to try to understand the physiological states giving rise to them. We have previously published several computational models to assist with such interpretation. Like many models in the realm of Systems Biology, these are complex and dependent on many parameters that can be difficult or impossible to measure precisely. Taking one such model, BrainSignals, as a starting point, we have developed several variant models in which specific regions of complexity are substituted with much simpler linear approximations. We demonstrate that model behaviour can be maintained whilst achieving a significant reduction in complexity, provided that the linearity assumptions hold. The simplified models have been tested for applicability with simulated data and experimental data from healthy adults undergoing a hypercapnia challenge, but relevance to different physiological and pathophysiological conditions will require specific testing. In conditions where the simplified models are applicable, their greater efficiency has potential to allow their use at the bedside to help interpret clinical data in near real-time.

Monitoring Cerebral Autoregulation After Brain Injury: Multimodal Assessment of Cerebral Slow-wave Oscillations Using Near-infrared Spectroscopy

Anesthesia and Analgesia. Jul, 2015  |  Pubmed ID: 25993387

Continuous monitoring of cerebral autoregulation might provide novel treatment targets and identify therapeutic windows after acute brain injury. Slow oscillations of cerebral hemodynamics (0.05-0.003 Hz) are visible in multimodal neuromonitoring and may be analyzed to provide novel, surrogate measures of autoregulation. Near-infrared spectroscopy (NIRS) is an optical neuromonitoring technique, which shows promise for widespread clinical applicability because it is noninvasive and easily delivered across a wide range of clinical scenarios. The aim of this study is to identify the relationship between NIRS signal oscillations and multimodal neuromonitoring, examining the utility of near infrared derived indices of cerebrovascular reactivity.

Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain During and Following Hypoxic-Ischaemia

PloS One. 2015  |  Pubmed ID: 26445281

Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS), and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue.

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