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1.  Simulation of Near-Infrared Light Absorption Considering Individual Head and Prefrontal Cortex Anatomy: Implications for Optical Neuroimaging 
PLoS ONE  2011;6(10):e26377.
Functional near-infrared spectroscopy (fNIRS) is an established optical neuroimaging method for measuring functional hemodynamic responses to infer neural activation. However, the impact of individual anatomy on the sensitivity of fNIRS measuring hemodynamics within cortical gray matter is still unknown. By means of Monte Carlo simulations and structural MRI of 23 healthy subjects (mean age: years), we characterized the individual distribution of tissue-specific NIR-light absorption underneath 24 prefrontal fNIRS channels. We, thereby, investigated the impact of scalp-cortex distance (SCD), frontal sinus volume as well as sulcal morphology on gray matter volumes () traversed by NIR-light, i.e. anatomy-dependent fNIRS sensitivity. The NIR-light absorption between optodes was distributed describing a rotational ellipsoid with a mean penetration depth of considering the deepest of light. Of the detected photon packages scalp and bone absorbed and absorbed of the energy. The mean volume was negatively correlated () with the SCD and frontal sinus volume () and was reduced by in subjects with relatively large compared to small frontal sinus. Head circumference was significantly positively correlated with the mean SCD () and the traversed frontal sinus volume (). Sulcal morphology had no significant impact on . Our findings suggest to consider individual SCD and frontal sinus volume as anatomical factors impacting fNIRS sensitivity. Head circumference may represent a practical measure to partly control for these sources of error variance.
PMCID: PMC3200329  PMID: 22039475
2.  Depth Sensitivity and Source-Detector Separations for Near Infrared Spectroscopy Based on the Colin27 Brain Template 
PLoS ONE  2013;8(8):e66319.
Understanding the spatial and depth sensitivity of non-invasive near-infrared spectroscopy (NIRS) measurements to brain tissue–i.e., near-infrared neuromonitoring (NIN) – is essential for designing experiments as well as interpreting research findings. However, a thorough characterization of such sensitivity in realistic head models has remained unavailable. In this study, we conducted 3,555 Monte Carlo (MC) simulations to densely cover the scalp of a well-characterized, adult male template brain (Colin27). We sought to evaluate: (i) the spatial sensitivity profile of NIRS to brain tissue as a function of source-detector separation, (ii) the NIRS sensitivity to brain tissue as a function of depth in this realistic and complex head model, and (iii) the effect of NIRS instrument sensitivity on detecting brain activation. We found that increasing the source-detector (SD) separation from 20 to 65 mm provides monotonic increases in sensitivity to brain tissue. For every 10 mm increase in SD separation (up to ∼45 mm), sensitivity to gray matter increased an additional 4%. Our analyses also demonstrate that sensitivity in depth (S) decreases exponentially, with a “rule-of-thumb” formula S = 0.75*0.85depth. Thus, while the depth sensitivity of NIRS is not strictly limited, NIN signals in adult humans are strongly biased towards the outermost 10–15 mm of intracranial space. These general results, along with the detailed quantitation of sensitivity estimates around the head, can provide detailed guidance for interpreting the likely sources of NIRS signals, as well as help NIRS investigators design and plan better NIRS experiments, head probes and instruments.
PMCID: PMC3731322  PMID: 23936292
3.  Patient-oriented simulation based on Monte Carlo algorithm by using MRI data 
Although Monte Carlo simulations of light propagation in full segmented three-dimensional MRI based anatomical models of the human head have been reported in many articles. To our knowledge, there is no patient-oriented simulation for individualized calibration with NIRS measurement. Thus, we offer an approach for brain modeling based on image segmentation process with in vivo MRI T1 three-dimensional image to investigate the individualized calibration for NIRS measurement with Monte Carlo simulation.
In this study, an individualized brain is modeled based on in vivo MRI 3D image as five layers structure. The behavior of photon migration was studied for this individualized brain detections based on three-dimensional time-resolved Monte Carlo algorithm. During the Monte Carlo iteration, all photon paths were traced with various source-detector separations for characterization of brain structure to provide helpful information for individualized design of NIRS system.
Our results indicate that the patient-oriented simulation can provide significant characteristics on the optimal choice of source-detector separation within 3.3 cm of individualized design in this case. Significant distortions were observed around the cerebral cortex folding. The spatial sensitivity profile penetrated deeper to the brain in the case of expanded CSF. This finding suggests that the optical method may provide not only functional signal from brain activation but also structural information of brain atrophy with the expanded CSF layer. The proposed modeling method also provides multi-wavelength for NIRS simulation to approach the practical NIRS measurement.
In this study, the three-dimensional time-resolved brain modeling method approaches the realistic human brain that provides useful information for NIRS systematic design and calibration for individualized case with prior MRI data.
PMCID: PMC3355000  PMID: 22510474
Patient-oriented simulation; Time-resolved Monte Carlo; Brain modeling; Spatial sensitivity profile
4.  The physiological origin of task-evoked systemic artefacts in functional near infrared spectroscopy 
Neuroimage  2012;61(1):70-81.
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.
► Task-evoked changes in the skin blood volume induce artefacts in fNIRS signals. ► Artefacts result from a venous volume decrease due to sympathetic vasoconstriction. ► This phenomenon might induce false positives in fNIRS experiments on the forehead.
PMCID: PMC3348501  PMID: 22426347
Time-domain optical brain imaging; Systemic changes; Skin blood flow; Periphery physiology; fMRI; Frontal lobe
5.  Short separation channel location impacts the performance of short channel regression in NIRS 
Neuroimage  2011;59(3):2518-2528.
Near-Infrared Spectroscopy (NIRS) allows the recovery of cortical oxy-and deoxyhemoglobin changes associated with evoked brain activity. NIRS is a back-reflection measurement making it very sensitive to the superficial layers of the head, i.e. the skin and the skull, where systemic interference occurs. As a result, the NIRS signal is strongly contaminated with systemic interference of superficial origin. A recent approach to overcome this problem has been the use of additional short source-detector separation optodes as regressors. Since these additional measurements are mainly sensitive to superficial layers in adult humans, they can be used to remove the systemic interference present in longer separation measurements, improving the recovery of the cortical hemodynamic response function (HRF). One question that remains to answer is whether or not a short separation measurement is required in close proximity to each long separation NIRS channel. Here, we show that the systemic interference occurring in the superficial layers of the human head is inhomogeneous across the surface of the scalp. As a result, the improvement obtained by using a short separation optode decreases as the relative distance between the short and the long measurement is increased. NIRS data was acquired on 6 human subjects both at rest and during a motor task consisting of finger tapping. The effect of distance between the short and the long channel was first quantified by recovering a synthetic hemodynamic response added over the resting-state data. The effect was also observed in the functional data collected during the finger tapping task. Together, these results suggest that the short separation measurement must be located as close as 1.5 cm from the standard NIRS channel in order to provide an improvement which is of practical use. In this case, the improvement in Contrast-to-Noise Ratio (CNR) compared to a standard General Linear Model (GLM) procedure without using any small separation optode reached 50 % for HbO and 100 % for HbR. Using small separations located farther than 2 cm away resulted in mild or negligible improvements only.
PMCID: PMC3254723  PMID: 21945793
Near-Infrared Spectroscopy; Systemic Interference; Short Optode Separations; Kalman filtering
6.  Coregistering functional near-infrared spectroscopy with underlying cortical areas in infants 
Neurophotonics  2014;1(2):025006-.
Functional near-infrared spectroscopy (fNIRS) is becoming a popular tool in developmental neuroscience for mapping functional localized brain responses. However, as it cannot provide information about underlying anatomy, researchers have begun to conduct spatial registration of fNIRS channels to cortical anatomy in adults. The current work investigated this issue with infants by coregistering fNIRS and magnetic resonance imaging (MRI) data from 55 individuals. Our findings suggest that fNIRS channels can be reliably registered with regions in the frontal and temporal cortex of infants from 4 to 7 months of age. Although some macro-anatomical regions are difficult to consistently define, others are more stable and fNIRS channels on an age-appropriate MRI template are often consistent with individual infant MRIs. We have generated a standardized scalp surface map of fNIRS channel locators to reliably locate cortical regions for fNIRS developmental researchers. This new map can be used to identify the inferior frontal gyrus, superior temporal sulcus (STS) region [which includes the superior and middle temporal gyri (MTG) nearest to the STS], and MTG and temporal-parietal regions in 4- to 7-month-old infants. Future work will model data for the whole head, taking into account the properties of light transport in tissue, and expanding to different ages across development.
PMCID: PMC4280679  PMID: 25558463
functional near-infrared spectroscopy; magnetic resonance imaging; coregistration; infancy; development
7.  Cerebral functional imaging using near-infrared spectroscopy during repeated performances of motor rehabilitation tasks tested on healthy subjects 
To investigate the relationship between the frontal and sensorimotor cortices and motor learning, hemodynamic responses were recorded from the frontal and sensorimotor cortices using functional near infrared spectroscopy (NIRS) while healthy subjects performed motor learning tasks used in rehabilitation medicine. Whole-head NIRS recordings indicated that response latencies in the anterior dorsomedial prefrontal cortex (aDMPFC) were shorter than in other frontal and parietal areas. Furthermore, the increment rate of the hemodynamic responses in the aDMPFC across the eight repeated trials significantly correlated with those in the other areas, as well as with the improvement rate of task performance across the 8 repeated trials. In the second experiment, to dissociate scalp- and brain-derived hemodynamic responses, hemodynamic responses were recorded from the head over the aDMPFC using a multi-distance probe arrangement. Six probes (a single source probe and 5 detectors) were linearly placed 6 mm apart from each of the neighboring probes. Using independent component analyses of hemodynamic signals from the 5 source-detector pairs, we dissociated scalp- and brain-derived components of the hemodynamic responses. Hemodynamic responses corrected for scalp-derived responses over the aDMPFC significantly increased across the 8 trials and correlated with task performance. In the third experiment, subjects were required to perform the same task with and without transcranial direct current stimulation (tDCS) of the aDMPFC before the task. The tDCS significantly improved task performance. These results indicate that the aDMPFC is crucial for improved performance in repetitive motor learning.
PMCID: PMC4026732  PMID: 24860474
frontal pole; NIRS; rehabilitation; motor skill; tDCS
8.  Quantification of the cortical contribution to the NIRS signal over the motor cortex using concurrent NIRS-fMRI measurements 
Neuroimage  2011;59(4):3933-3940.
Near-Infrared Spectroscopy (NIRS) measures the functional hemodynamic response occuring at the surface of the cortex. Large pial veins are located above the surface of the cerebral cortex. Following activation, these veins exhibit oxygenation changes but their volume likely stays constant. The back-reflection geometry of the NIRS measurement renders the signal very sensitive to these superficial pial veins. As such, the measured NIRS signal contains contributions from both the cortical region as well as the pial vasculature. In this work, the cortical contribution to the NIRS signal was investigated using (1) Monte Carlo simulations over a realistic geometry constructed from anatomical and vascular MRI and (2) multimodal NIRS-BOLD recordings during motor stimulation. A good agreement was found between the simulations and the modeling analysis of in vivo measurements. Our results suggest that the cortical contribution to the deoxyhemoglobin signal change (ΔHbR) is equal to 16–22% of the cortical contribution to the total hemoglobin signal change (ΔHbT). Similarly, the cortical contribution of the oxyhemoglobin signal change (ΔHbO) is equal to 73–79% of the cortical contribution to the ΔHbT signal. These results suggest that ΔHbT is far less sensitive to pial vein contamination and therefore, it is likely that the ΔHbT signal provides better spatial specificity and should be used instead of ΔHbO or ΔHbR to map cerebral activity with NIRS. While different stimuli will result in different pial vein contributions, our finger tapping results do reveal the importance of considering the pial contribution.
PMCID: PMC3279595  PMID: 22036999
NIRS-fMRI; Pial vasculature; Balloon Model; Monte Carlo simulations
9.  A quantitative comparison of NIRS and fMRI across multiple cognitive tasks 
NeuroImage  2010;54(4):2808-2821.
Near infrared spectroscopy (NIRS) is an increasingly popular technology for studying brain function. NIRS presents several advantages relative to functional magnetic resonance imaging (fMRI), such as measurement of concentration changes in both oxygenated- and deoxygenated hemoglobin, finer temporal resolution, and ease of administration, as well as disadvantages, most prominently inferior spatial resolution and decreased signal-to-noise ratio (SNR). While fMRI has become the gold standard for in vivo imaging of the human brain, in practice NIRS is a more convenient and less expensive technology than fMRI. It is therefore of interest to many researchers how NIRS compares to fMRI in studies of brain function. In the present study we scanned participants with simultaneous NIRS and fMRI on a battery of cognitive tasks, placing NIRS probes over both frontal and parietal brain regions. We performed detailed comparisons of the signals in both temporal and spatial domains. We found that NIRS signals have significantly weaker SNR, but are nonetheless often highly correlated with fMRI measurements. Both SNR and the distance between the scalp and the brain contributed to variability in the NIRS/fMRI correlations. In the spatial domain, we found that a photon path forming an ellipse between the NIRS emitter and detector correlated most strongly with the BOLD response. Taken together these findings suggest that, while NIRS can be an appropriate substitute for fMRI for studying brain activity related to cognitive tasks, care should be taken when designing studies with NIRS to ensure that: 1) the spatial resolution is adequate for answering the question of interest and 2) the design accounts for weaker SNR, especially in brain regions more distal from the scalp.
PMCID: PMC3021967  PMID: 21047559
10.  Intra- and extra-cranial effects of transient blood pressure changes on brain near-infrared spectroscopy (NIRS) measurements 
Journal of Neuroscience Methods  2011;197(2):283-288.
► We recorded NIRS from the visual cortex during pattern-reversal stimulation. ► Transient blood pressure changes were induced by arm-raising. ► Blood pressure changes significantly altered deep and shallow NIRS recordings. ► The effect appears to originate from both intra- and extra-cranial regions. ► Blood pressure must be considered as a potential confound in NIRS studies.
Brain near-infrared spectroscopy (NIRS) is an emerging neurophysiological tool that combines straightforward activity localization with cost–economy, portability and patient compatibility. NIRS is proving its empirical utility across specific cognitive and emotional paradigms. However, a potential limitation is that it is not only sensitive to haemodynamic changes taking place in the cortex, and task-related cardiovascular responses expressed in the perfusion of extracranial layers may be confounding. Existing literature reports correlations between brain NIRS and systemic blood pressure, yet it falls short of establishing whether in normal participants the blood pressure changes encountered in experimental settings can have confounding effects. Here, we tested this hypothesis by performing two experimental manipulations while recording from superficial occipital cortex, encompassing striate and extrastriate regions. Visual stimulation with reversing chequerboards evoked cortical haemodynamic responses. Simultaneously and independently, transient systemic blood pressure changes were generated through rapid arm-raising. Shallow-penetration NIRS recordings, probing only extra-cerebral tissues, highlighted close haemodynamic coupling with blood pressure. A different coupling pattern was observed in deep-penetration recordings directed at haemodynamic signals from visual cortex. In absence of blood-pressure changes, NIRS signals tracked differences in visual stimulus duration. However when blood pressure was actively manipulated, this effect was absent and replaced by a very large pressure-related response. Our observations demonstrate that blood pressure fluctuations can exert confounding effects on brain NIRS, through expression in extracranial tissues and within the brain itself. We highlight the necessity for continuous blood pressure monitoring alongside brain NIRS, and for further research on methods to correct for physiological confounds.
PMCID: PMC3089735  PMID: 21392529
Near-infrared spectroscopy (NIRS); Blood pressure; Autonomic arousal; Visual stimulation
11.  The sinonasal communication in the horse: examinations using computerized three-dimensional reformatted renderings of computed-tomography datasets 
Sinusitis is a common disease in the horse. In human medicine it is described, that obstruction of the sinonasal communication plays a major role in the development of sinusitis. To get spatial sense of the equine specific communication ways between the nasal cavity and the paranasal sinuses, heads of 19 horses, aged 2 to 26 years, were analyzed using three-dimensional (3D) reformatted renderings of CT-datasets. Three-dimensional models were generated following manual and semi-automated segmentation. Before segmentation, the two-dimensional (2D) CT-images were verified against corresponding frozen sections of cadaveric heads.
Three-dimensional analysis of the paranasal sinuses showed the bilateral existence of seven sinus compartments: rostral maxillary sinus, ventral conchal sinus, caudal maxillary sinus, dorsal conchal sinus, frontal sinus, sphenopalatine sinus and middle conchal sinus. The maxillary septum divides these seven compartments into two sinus systems: a rostral paranasal sinus system composed of the rostral maxillary sinus and the ventral conchal sinus and a caudal paranasal sinus system which comprises all other sinuses. The generated 3D models revealed a typically configuration of the sinonasal communication ways. The sinonasal communication started within the middle nasal meatus at the nasomaxillary aperture (Apertura nasomaxillaris), which opens in a common sinonasal channel (Canalis sinunasalis communis). This common sinonasal channel ramifies into a rostral sinonasal channel (Canalis sinunasalis rostralis) and a caudo-lateral sinonasal channel (Canalis sinunasalis caudalis). The rostral sinonasal channel ventilated the rostral paranasal sinus system, the caudo-lateral sinonasal channel opened into the caudal paranasal sinus system. The rostral sinonasal channel was connected to the rostral paranasal sinuses in various ways. Whereas, the caudal channel showed less anatomical variations and was in all cases connected to the caudal maxillary sinus. Volumetric measurements of the sinonasal channels showed no statistically significant differences (P <0.05) between the right and left side of the head.
Under physiologic conditions both paranasal sinus systems are connected to the nasal cavity by equine specific sinonasal channels. To resolve sinus disease it is aimed to maintain or even reconstruct the normal anatomy of the sinonasal communication by surgical intervention. Therefore, the presented 3D analyses may provide a useful basis.
PMCID: PMC3995307  PMID: 24646003
Horse; Computed tomography; Nasomaxillary aperture; Apertura nasomaxillaris; Upper airway; Sinonasal channel system; Paranasal sinuses
12.  Further improvement in reducing superficial contamination in NIRS using double short separation measurements 
NeuroImage  2013;85(0 1):10.1016/j.neuroimage.2013.01.073.
Near-Infrared Spectroscopy (NIRS) allows the recovery of the evoked hemodynamic response to brain activation. In adult human populations, the NIRS signal is strongly contaminated by systemic interference occurring in the superficial layers of the head. An approach to overcome this difficulty is to use additional NIRS measurements with short optode separations to measure the systemic hemodynamic fluctuations occurring in the superficial layers. These measurements can then be used as regressors in the post-experiment analysis to remove the systemic contamination and isolate the brain signal. In our previous work, we showed that the systemic interference measured in NIRS is heterogeneous across the surface of the scalp. As a consequence, the short separation measurement used in the regression procedure must be located close to the standard NIRS channel from which the evoked hemodynamic response of the brain is to be recovered. Here, we demonstrate that using two short separation measurements, one at the source optode and one at the detector optode, further increases the performance of the short separation regression method compared to using a single short separation measurement. While a single short separation channel produces an average reduction in noise of 33% for HbO, using a short separation channel at both source and detector reduces noise by 59% compared to the standard method using a general linear model (GLM) without short separation. For HbR, noise reduction of 3% is achieved using a single short separation and this number goes to 47% when two short separations are used. Our work emphasizes the importance of integrating short separation measurements both at the source and at the detector optode of the standard channels from which the hemodynamic response is to be recovered. While the implementation of short separation sources presents some difficulties experimentally, the improvement in noise reduction is significant enough to justify the practical challenges.
PMCID: PMC3665655  PMID: 23403181
Near-Infrared Spectroscopy; Systemic Interference; Short Optode Separations; Kalman filtering; State-Space analysis
13.  Experimental investigation of NIRS spatial sensitivity 
Biomedical Optics Express  2011;2(6):1478-1493.
Near infrared spectroscopy (NIRS) is regarded as a potential medical diagnostic technique for investigation of hemodynamic changes. However, uncertainties pertaining to the origin of NIRS signals have hampered its clinical interpretation. The uncertainities in NIRS measurements especially in case of living tissues are due to lack of rigorous combined theoretical-experimental studies resulting in clear understanding of the origin of NIRS signals. For their reliable interpretation it is important to understand the relationship between spatial changes in optical properties and corresponding changes in the NIRS signal. We investigated spatial sensitivity of near infrared optical measurements using an experimental approach. It uses a liquid optical phantom as tissue equivalent, which is explored under robot-control by a small, approximately point like perturbation of desired optical properties, and a NIRS instrument for trans-illumination/reflection measurements. The experimentally obtained sensitivity has been analyzed and compared with numerical simulations. In preliminary experiments we investigated the influence of various optical properties of the medium and of source/detector distances on the spatial sensitivity distribution. The acquired sensitivity maps can be used to define characteristic parameters. As an example, we used a 25% threshold to define a penetration depth measure which provides values in good accordance with published ones. To the best of our knowledge this is the first experimental study of NIRS spatial sensitivity. The presented method will allow in depth experimental investigation of the influence of various conditions pertaining to medium such as optical properties of tissue (scattering and absorption) and of the source/detector configuration.
PMCID: PMC3114217  PMID: 21698012
(120.3890) Medical optics instrumentation; (170.3660) Light propagation in tissues; (300.1030) Absorption
14.  Functional near-infrared spectroscopy for the assessment of overt reading 
Brain and Behavior  2012;2(6):825-837.
Functional near-infrared spectroscopy (fNIRS) has become increasingly established as a promising technique for monitoring functional brain activity. To our knowledge, no study has yet used fNIRS to investigate overt reading of irregular words and nonwords with a full coverage of the cerebral regions involved in reading processes. The aim of our study was to design and validate a protocol using fNIRS for the assessment of overt reading. Twelve healthy French-speaking adults underwent one session of fNIRS recording while performing an overt reading of 13 blocks of irregular words and nonwords. Reading blocks were separated by baseline periods during which participants were instructed to fixate a cross. Sources (n = 55) and detectors (n = 16) were placed bilaterally over frontal, temporal, parietal, and occipital regions. Two wavelengths were used: 690 nm, more sensitive to deoxyhemoglobin (HbR) concentration changes, and 830 nm, more sensitive to oxyhemoglobin (HbO) concentration changes. For all participants, total hemoglobin (HbT) concentrations (HbO + HbR) were significantly higher than baseline for both irregular word and nonword reading in the inferior frontal gyri, the middle and superior temporal gyri, and the occipital cortices bilaterally. In the temporal gyri, although the difference was not significant, [HbT] values were higher in the left hemisphere. In the bilateral inferior frontal gyri, higher [HbT] values were found in nonword than in irregular word reading. This activation could be related to the grapheme-to-phoneme conversion characterizing the phonological pathway of reading. Our findings confirm that fNIRS is an appropriate technique to assess the neural correlates of overt reading.
PMCID: PMC3500469  PMID: 23170245
Adults; irregular words; lexical reading; nonwords; optical imaging; phonological reading; reading aloud
15.  Cytochrome c oxidase response to changes in cerebral oxygen delivery in the adult brain shows higher brain-specificity than haemoglobin☆ 
Neuroimage  2014;85(Pt 1):234-244.
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.
•NIRS was used to measure oxidised cytochrome c oxidase (Δ[oxCCO]) in healthy brain.•Δ[oxCCO] changed in the same direction as changes in cerebral oxygen delivery.•Magnitude of Δ[oxCCO] response increased with increasing light penetration depth.•Corresponding haemoglobin changes showed no dependence on light penetration depth.•NIRS-measured Δ[oxCCO] has higher brain specificity than haemoglobin.
PMCID: PMC3898943  PMID: 23707584
Cytochrome c oxidase; Hypoxia; Hyperoxia; Hypocapnia; Hypercapnia; Near-infrared spectroscopy
16.  Accuracy of oxygen saturation and total hemoglobin estimates in the neonatal brain using the semi-infinite slab model for FD-NIRS data analysis 
Biomedical Optics Express  2014;5(12):4300-4312.
Frequency domain near-infrared spectroscopy (FD-NIRS) is a non-invasive method for measuring optical absorption in the brain. Common data analysis procedures for FD-NIRS data assume the head is a semi-infinite, homogenous medium. This assumption introduces bias in estimates of absorption (μa), scattering ( μs′), tissue oxygen saturation (StO2), and total hemoglobin (HbT). Previous works have investigated the accuracy of recovered μa values under this assumption. The purpose of this study was to examine the accuracy of recovered StO2 and HbT values in FD-NIRS measurements of the neonatal brain. We used Monte Carlo methods to compute light propagation through a neonate head model in order to simulate FD-NIRS measurements at 690 nm and 830 nm. We recovered μa, μs′, StO2, and HbT using common analysis procedures that assume a semi-infinite, homogenous medium and compared the recovered values to simulated values. Additionally, we characterized the effects of curvature via simulations on homogenous spheres of varying radius. Lastly, we investigated the effects of varying amounts of extra-axial fluid. Curvature induced underestimation of μa, μs′, and HbT, but had minimal effects on StO2. For the morphologically normal neonate head model, the mean absolute percent errors (MAPE) of recovered μa values were 12% and 7% for 690 nm and 830 nm, respectively, when source-detector separation was at least 20 mm. The MAPE for recovered StO2 and HbT were 6% and 9%, respectively. Larger relative errors were observed (∼20–30%), especially as StO2 and HbT deviated from normal values. Excess CSF around the brain caused very large errors in μa, μs′, and HbT, but had little effect on StO2.
PMCID: PMC4285606  PMID: 25574439
(170.3660) Light propagation in tissues; (170.5380) Physiology; (300.0300) Spectroscopy
17.  Correspondence of electroencephalography and near-infrared spectroscopy sensitivities to the cerebral cortex using a high-density layout 
Neurophotonics  2014;1(2):025001-.
This study investigates the correspondence of the cortical sensitivity of electroencephalography (EEG) and near-infrared spectroscopy (NIRS). EEG forward model sensitivity to the cerebral cortex was calculated for 329 EEG electrodes following the 10-5 EEG positioning system using a segmented structural magnetic resonance imaging scan of a human subject. NIRS forward model sensitivity was calculated for the same subject using 156 NIRS source-detector pairs selected from 32 source and 32 detector optodes positioned on the scalp using a subset of the 10-5 EEG positioning system. Sensitivity correlations between colocalized NIRS source-detector pair groups and EEG channels yielded R = 0.46 ± 0.08. Groups of NIRS source-detector pairs with maximum correlations to EEG electrode sensitivities are tabulated. The mean correlation between the point spread functions for EEG and NIRS regions of interest (ROI) was R = 0.43 ± 0.07. Spherical ROIs with radii of 26 mm yielded the maximum correlation between EEG and NIRS averaged across all cortical mesh nodes. These sensitivity correlations between EEG and NIRS should be taken into account when designing multimodal studies of neurovascular coupling and when using NIRS as a statistical prior for EEG source localization.
PMCID: PMC4280681  PMID: 25558462
electroencephalography; near-infrared spectroscopy; diffuse optical tomography; forward model; inverse model; sensitivity
18.  Intraoperative Transillumination to Determine the Extent of Frontal Sinus in Subcranial Approach to Anterior Skull Base 
Skull Base  2011;21(2):71-74.
We sought to determine the extent of the frontal sinus by intraoperative transillumination through the superomedial orbital wall in a subcranial approach to the anterior skull base. After raising a bicoronal flap, the frontal sinus was transilluminated through the superomedial orbital wall with a fiber-optic light source, delineating the extent of the frontal sinus. The frontal sinus boundary was marked with a marker pen. A frontal sinus anterior wall osteotomy was performed with a sagittal saw, staying within the confines of the frontal sinus marking. A bone flap was removed, and the posterior wall was drilled out. The remaining procedure was performed in a standard fashion. At the end of the procedure, the bone flap was fixed with a titanium plate. A total of 58 patients had undergone craniofacial resection from January 2004 to December 2007. In 13 patients, a subcranial approach was employed using the transillumination technique. Transillumination was successful in delineating the frontal sinus periphery in all 13 patients. Intraoperative transillumination of the frontal sinus through the superomedial orbital wall is a simple and effective method to delineate the frontal sinus periphery in a subcranial approach to the anterior skull base.
PMCID: PMC3312596  PMID: 22451803
Transillumination of frontal sinus; subcranial approach; frontal craniotomy; osteoplastic flap; anterior skull base
19.  Brain Specificity of Diffuse Optical Imaging: Improvements from Superficial Signal Regression and Tomography 
Functional near infrared spectroscopy (fNIRS) is a portable monitor of cerebral hemodynamics with wide clinical potential. However, in fNIRS, the vascular signal from the brain is often obscured by vascular signals present in the scalp and skull. In this paper, we evaluate two methods for improving in vivo data from adult human subjects through the use of high-density diffuse optical tomography (DOT). First, we test whether we can extend superficial regression methods (which utilize the multiple source–detector pair separations) from sparse optode arrays to application with DOT imaging arrays. In order to accomplish this goal, we modify the method to remove physiological artifacts from deeper sampling channels using an average of shallow measurements. Second, DOT provides three-dimensional image reconstructions and should explicitly separate different tissue layers. We test whether DOT's depth-sectioning can completely remove superficial physiological artifacts. Herein, we assess improvements in signal quality and reproducibility due to these methods using a well-characterized visual paradigm and our high-density DOT system. Both approaches remove noise from the data, resulting in cleaner imaging and more consistent hemodynamic responses. Additionally, the two methods act synergistically, with greater improvements when the approaches are used together.
PMCID: PMC2914577  PMID: 20725524
neuroimaging; biomedical optics; near-infrared spectroscopy; diffuse optical tomography; artifact removal; image quality
20.  Near-infrared spectroscopy measurement of the pulsatile component of cerebral blood flow and volume from arterial oscillations 
Journal of biomedical optics  2007;12(1):014033.
We describe a near-infrared spectroscopy (NIRS) method to noninvasively measure relative changes in the pulsate components of cerebral blood flow (pCBF) and volume (pCBV) from the shape of heartbeat oscillations. We present a model that is used and data to show the feasibility of the method. We use a continuous-wave NIRS system to measure the arterial oscillations originating in the brains of piglets. Changes in the animals' CBF are induced by adding CO2 to the breathing gas. To study the influence of scalp on our measurements, comparative, invasive measurements are performed on one side of the head simultaneously with noninvasive measurements on the other side. We also did comparative measurements of CBF using a laser Doppler system to validate the results of our method. The results indicate that for sufficient source-detector separation, the signal contribution of the scalp is minimal and the measurements are representative of the cerebral hemodynamics. Moreover, good correlation between the results of the laser Doppler system and the NIRS system indicate that the presented method is capable of measuring relative changes in CBF. Preliminary results show the potential of this NIRS method to measure pCBF and pCBV relative changes in neonatal pigs.
PMCID: PMC2637815  PMID: 17343508
cerebral blood flow; cerebral blood volume; near-infrared spectroscopy; arterial oscillations
21.  An Exploration of the Effect of Hemodynamic Changes Due to Normal Aging on the fNIRS Response to Semantic Processing of Words 
Like other neuroimaging techniques assessing cerebral blood oxygenation, near-infrared spectroscopy (NIRS) has been applied in many neurocognitive studies. With NIRS, neural activation can be explored indirectly via hemodynamic changes in the imaged region. In studies of aging, changes in baseline physiology and brain anatomy confound NIRS measures seeking to investigate age-related changes in neuronal activity. The field is thus hampered by the complexity of the aging process itself, and statistical inferences from functional data acquired by optical imaging techniques must be interpreted with care. Multimodal integration of NIRS with both structural and baseline physiological assessments is crucial to avoid misinterpreting neuroimaging signals. In this study, a combination of two different optical techniques, anatomical MRI and Arterial Spin Labeling (ASL), was used to investigate age-related changes in activation during a lexical-semantic processing task. Quantitative analysis revealed decreased baseline oxyhemoglobin and cerebral blood flow in the older adults. Using baseline physiology measures as regressors in the investigation of functional concentration changes when doing analyses of variance, we found significant changes in task-induced areas of activity. In the right hemisphere, more significant age-related activity was observed around the junction of the inferior frontal gyrus and inferior precentral sulcus, along with engagement of Wernicke’s area. In the left hemisphere, the degree and extent of frontal activation, including the dorsolateral prefrontal cortex and inferior frontal gyrus, differed between age groups. Measuring background physiological differences and using their values as regressors in statistical analyses allowed a more appropriate, age-corrected understanding of the functional differentiations between age groups. Age-corrected baselines are thus essential to investigate which components of the NIRS signal are altered by aging.
PMCID: PMC4248672  PMID: 25520697
cognitive aging; language; semantics; functional NIRS; anatomical MRI; baseline physiology; hemodynamic response; ASL
22.  Dependence on NIRS Source-Detector Spacing of Cytochrome c Oxidase Response to Hypoxia and Hypercapnia in the Adult Brain 
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.
PMCID: PMC4037984  PMID: 23852515
23.  Changes in tissue oxyhaemoglobin concentration measured using multichannel near infrared spectroscopy during internal carotid angiography 
OBJECTIVE—To develop an in vivo model for testing spatially resolved spectroscopy and quantified near infrared spectroscopy (NIRS) cerebral blood flow measurements.
METHOD—Multiple detector NIRS has been used to study changes in tissue oxyhaemoglobin (O2Hb) concentration during selective internal carotid angiography. A significant reduction in O2Hb occurred in tissue interrogated by detectors situated between 0.7 and 4.1cm from the NIRS light source.
RESULTS—The time course of O2Hb concentration change was consistent with displacement of oxygenated blood by the radiocontrast medium from vascular beds of differing flow and NIR light attenuation. Increasing changes in O2Hb concentration per unit photon path length—predicted to occur at greater emitter-detector separations if those changes had occurred predominantly in cerebral tissue—were found in the first four seconds after injection of radiocontrast medium. However, later changes (6-10 s) were larger and were not proportional to emitter-detector separation.
CONCLUSION—The findings indicate that simple assumptions regarding the distribution of the internal carotid artery blood supply to cerebral and extracerebral tissues, the photon path length through those tissues, and their relative contributions to attenuation of NIR light may not be justified.

PMCID: PMC2169830  PMID: 9408110
24.  Origins of Spatial Working Memory Deficits in Schizophrenia: An Event-Related fMRI and Near-Infrared Spectroscopy Study 
PLoS ONE  2008;3(3):e1760.
Abnormal prefrontal functioning plays a central role in the working memory (WM) deficits of schizophrenic patients, but the nature of the relationship between WM and prefrontal activation remains undetermined. Using two functional neuroimaging methods, we investigated the neural correlates of remembering and forgetting in schizophrenic and healthy participants. We focused on the brain activation during WM maintenance phase with event-related functional magnetic resonance imaging (fMRI). We also examined oxygenated hemoglobin changes in relation to memory performance with the near-infrared spectroscopy (NIRS) using the same spatial WM task. Distinct types of correct and error trials were segregated for analysis. fMRI data indicated that prefrontal activation was increased during WM maintenance on correct trials in both schizophrenic and healthy subjects. However, a significant difference was observed in the functional asymmetry of frontal activation pattern. Healthy subjects showed increased activation in the right frontal, temporal and cingulate regions. Schizophrenic patients showed greater activation compared with control subjects in left frontal, temporal and parietal regions as well as in right frontal regions. We also observed increased ‘false memory’ errors in schizophrenic patients, associated with increased prefrontal activation and resembling the activation pattern observed on the correct trials. NIRS data replicated the fMRI results. Thus, increased frontal activity was correlated with the accuracy of WM in both healthy control and schizophrenic participants. The major difference between the two groups concerned functional asymmetry; healthy subjects recruited right frontal regions during spatial WM maintenance whereas schizophrenic subjects recruited a wider network in both hemispheres to achieve the same level of memory performance. Increased “false memory” errors and accompanying bilateral prefrontal activation in schizophrenia suggest that the etiology of memory errors must be considered when comparing group performances. Finally, the concordance of fMRI and NIRS data supports NIRS as an alternative functional neuroimaging method for psychiatric research.
PMCID: PMC2257999  PMID: 18335036
25.  Does the resting state connectivity have hemispheric asymmetry? A near-infrared spectroscopy study 
NeuroImage  2013;85(0 1):10.1016/j.neuroimage.2013.05.092.
Near-infrared spectroscopy (NIRS) is a novel technology for low-cost noninvasive brain imaging suitable for use in virtually all subject and patient populations. Numerous studies of brain functional connectivity using fMRI, and recently NIRS, suggest new tools for the assessment of cognitive functions during task performance and the resting state (RS). We analyzed functional connectivity and its possible hemispheric asymmetry measuring coherence of optical signals at low frequencies (0.01-0.1 Hz) in the prefrontal cortex in 13 right-handed (RH) and 2 left-handed (LH) healthy subjects at rest (4-8 min) using a continuous-wave NIRS instrument CW5 (TechEn, Milford, MA). Two optical probes were placed bilaterally over the inferior frontal gyrus (IFG) and the middle frontal gyrus (MFG) using anatomical landmarks of the 10-20 system. As a result, 28 optical channels (14 for each hemisphere) were recorded for changes in oxygenated (HbO) and de-oxygenated (HbR) hemoglobin. Global physiological signals (respiratory and cardiac) were removed using Principal and Independent Component Analyses. Inter-channel coherences for HbO and HbR signals were calculated using Morlet wavelets along with correlation coefficients. Connectivity matrices showed specific patterns of connectivity which was higher within each anatomical region (IFG and MFG) and between hemispheres (e.g., left IFG <-> right IFG) than between IFG and MFG in the same hemisphere. Laterality indexes were calculated as t-values for the ‘left > right’ comparisons of intrinsic connectivity within each regional group of channels in each subject. Regardless of handedness, the group average laterality indexes were negative thus revealing significantly higher connectivity in the right hemisphere in the majority of RH subjects and in both LH subjects. The analysis of Granger Causality between hemispheres has also shown a greater flow of information from the right to the left hemisphere which may point to an important role of the right hemisphere in the resting state. These data encourage further exploration of the NIRS connectivity and its application for the analysis of hemispheric relationships within the functional architecture of the brain.
PMCID: PMC3869394  PMID: 23721726
Near-infrared spectroscopy; Brain hemodynamics; Functional connectivity; Resting state; Prefrontal cortex; Hemispheric asymmetry

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