As near-infrared spectroscopy (NIRS) broadens its application area to different age and disease groups, motion artifacts in the NIRS signal due to subject movement is becoming an important challenge. Motion artifacts generally produce signal fluctuations that are larger than physiological NIRS signals, thus it is crucial to correct for them before obtaining an estimate of stimulus evoked hemodynamic responses. There are various methods for correction such as principle component analysis (PCA), wavelet-based filtering and spline interpolation. Here, we introduce a new approach to motion artifact correction, targeted principle component analysis (tPCA), which incorporates a PCA filter only on the segments of data identified as motion artifacts. It is expected that this will overcome the issues of filtering desired signals that plagues standard PCA filtering of entire data sets. We compared the new approach with the most effective motion artifact correction algorithms on a set of data acquired simultaneously with a collodion-fixed probe (low motion artifact content) and a standard Velcro probe (high motion artifact content). Our results show that tPCA gives statistically better results in recovering hemodynamic response function (HRF) as compared to wavelet-based filtering and spline interpolation for the Velcro probe. It results in a significant reduction in mean-squared error (MSE) and significant enhancement in Pearson's correlation coefficient to the true HRF. The collodion-fixed fiber probe with no motion correction performed better than the Velcro probe corrected for motion artifacts in terms of MSE and Pearson's correlation coefficient. Thus, if the experimental study permits, the use of a collodion-fixed fiber probe may be desirable. If the use of a collodion-fixed probe is not feasible, then we suggest the use of tPCA in the processing of motion artifact contaminated data.
Papers from four different groups were published in 1993 demonstrating the ability of functional near infrared spectroscopy (fNIRS) to non-invasively measure hemoglobin concentration responses to brain function in humans. This special issue commemorates the first 20years of fNIRS research. The 9 reviews and 49 contributed papers provide a comprehensive survey of the exciting advances driving the field forward and of the myriad of applications that will benefit from fNIRS.
Calibrated functional magnetic resonance imaging (fMRI) is a widely used method to investigate brain function in terms of physiological quantities such as the cerebral metabolic rate of oxygen (CMRO2). The first and one of the most common methods of fMRI calibration is hypercapnic calibration. This is achieved via simultaneous measures of the blood-oxygenation-level dependent (BOLD) and the arterial spin labeling (ASL) signals during a functional task that evokes regional changes in CMRO2. A subsequent acquisition is then required during which the subject inhales carbon dioxide for short periods of time. A calibration constant, typically labeled M, is then estimated from the hypercapnic data and is subsequently used together with the BOLD-ASL recordings to compute evoked changes in CMRO2 during the functional task. The computation of M assumes a constant CMRO2 during the CO2 inhalation, an assumption that has been questioned since the origin of calibrated fMRI. In this study we used diffuse optical tomography (DOT) together with BOLD and ASL - an alternative calibration method that does not require any gas manipulation and therefore no constant CMRO2 assumption - to cross-validate the estimation of M obtained from a traditional hypercapnic calibration. We found a high correlation between the M values (R=0.87, p<0.01) estimated using these two approaches. The findings serve to validate the hypercapnic fMRI calibration technique and suggest that the inter-subject variability routinely obtained for M is reproducible with an alternative method and might therefore reflect inter-subject physiological variability.
We present a novel optical coherence tomography (OCT)-based technique for rapid volumetric imaging of red blood cell (RBC) flux in capillary networks. Previously we reported that OCT can capture individual RBC passage within a capillary, where the OCT intensity signal at a voxel fluctuates when an RBC passes the voxel. Based on this finding, we defined a metric of statistical intensity variation (SIV) and validated that the mean SIV is proportional to the RBC flux [RBC/s] through simulations and measurements. From rapidly scanned volume data, we used Hessian matrix analysis to vectorize a segment path of each capillary and estimate its flux from the mean of the SIVs gathered along the path. Repeating this process led to a 3D flux map of the capillary network. The present technique enabled us to trace the RBC flux changes over hundreds of capillaries with a temporal resolution of ~1 s during functional activation.
We established a strategy to perform cross-validation of serial optical coherence scanner imaging (SOCS) and diffusion tensor imaging (DTI) on a postmortem human medulla. Following DTI, the sample was serially scanned by SOCS, which integrates a vibratome slicer and a multi-contrast optical coherence tomography rig for large-scale three-dimensional imaging at microscopic resolution. The DTI dataset was registered to the SOCS space. An average correlation coefficient of 0.9 was found between the co-registered fiber maps constructed by fractional anisotropy and retardance contrasts. Pixelwise comparison of fiber orientations demonstrated good agreement between the DTI and SOCS measures. Details of the comparison were studied in regions exhibiting a variety of fiber organizations. DTI estimated the preferential orientation of small fiber tracts; however, it didn't capture their complex patterns as SOCS did. In terms of resolution and imaging depth, SOCS and DTI complement each other, and open new avenues for cross-modality investigations of the brain.
A great deal is known about the functional organization of cortical networks that mediate visual object processing in the adult. The current research is part of a growing effort to identify the functional maturation of these pathways in the developing brain. The current research used near-infrared spectroscopy to investigate functional activation of the infant cortex during the processing of featural information (shape) and spatiotemporal information (speed of motion) during the first year of life. Our investigation focused on two areas that were implicated in previous studies: anterior temporal cortex and posterior parietal cortex. Neuroimaging data were collected with 207 infants across three age groups: 3-6 months (Experiment 1), 7-8 months (Experiment 2), and 10-12 months (Experiments 3 and 4). The neuroimaging data revealed age-related changes in patterns of activation to shape and speed information, mostly involving posterior parietal areas, some of which were predicted and others that were not. We suggest that these changes reflect age-related differences in the perceptual and/or cognitive processes engaged during the task.
Near-infrared spectroscopy (NIRS) estimations of the adult brain baseline optical properties based on a homogeneous model of the head are known to introduce significant contamination from extracerebral layers. More complex models have been proposed and occasionally applied to in vivo data, but their performances have never been characterized on realistic head structures. Here we implement a flexible fitting routine of time-domain NIRS data using graphics processing unit based Monte Carlo simulations. We compare the results for two different geometries: a two-layer slab with variable thickness of the first layer and a template atlas head registered to the subject's head surface. We characterize the performance of the Monte Carlo approaches for fitting the optical properties from simulated time-resolved data of the adult head. We show that both geometries provide better results than the commonly used homogeneous model, and we quantify the improvement in terms of accuracy, linearity, and cross-talk from extracerebral layers.
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative has focused scientific attention on the necessary tools to understand the human brain and mind. Here, we outline our collective vision for what we can achieve within a decade with properly targeted efforts and discuss likely technological deliverables and neuroscience progress.
Spectral domain optical coherence tomography (SD-OCT) is a high resolution imaging technique that generates excellent contrast based on intrinsic optical properties of the tissue, such as neurons and fibers. The SD-OCT data acquisition is performed directly on the tissue block, diminishing the need for cutting, mounting and staining. We utilized SD-OCT to visualize the laminar structure of the isocortex and compared cortical cytoarchitecture with the gold standard Nissl staining, both qualitatively and quantitatively. In histological processing, distortions routinely affect registration to the blockface image and prevent accurate 3D reconstruction of regions of tissue. We compared blockface registration to SD-OCT and Nissl, respectively, and found that SD-OCT-blockface registration was significantly more accurate than Nissl-blockface registration. Two independent observers manually labeled cortical laminae (e.g. III, IV and V) in SD-OCT images and Nissl stained sections. Our results show that OCT images exhibit sufficient contrast in the cortex to reliably differentiate the cortical layers. Furthermore, the modalities were compared with regard to cortical laminar organization and showed good agreement. Taken together, these SD-OCT results suggest that SD-OCT contains information comparable to standard histological stains such as Nissl in terms of distinguishing cortical layers and architectonic areas. Given these data, we propose that SD-OCT can be used to reliably generate 3D reconstructions of multiple cubic centimeters of cortex that can be used to accurately and semi-automatically perform standard histological analyses.
Aging is one of the major risk factors for white matter injury in cerebrovascular disease. However, the effects of age on the mechanisms of injury/repair in white matter remain to be fully elucidated. Here, we ask whether, compared with young brains, white matter regions in older brains may be more vulnerable in part because of decreased rates of compensatory oligodendrogenesis after injury.
As capillaries exhibit heterogeneous and fluctuating dynamics even during baseline, a technique measuring red blood cell (RBC) speed and flux over many capillaries at the same time is needed. Here, we report that optical coherence tomography can capture individual RBC passage simultaneously over many capillaries located at different depths. Further, we demonstrate the ability to quantify RBC speed, flux, and linear density. This technique will provide a means to monitor microvascular flow dynamics over many capillaries at different depths at the same time.
Calcium-dependent release of vasoactive gliotransmitters is widely assumed to trigger vasodilation associated with rapid increases in neuronal activity. Inconsistent with this hypothesis, intact stimulus-induced vasodilation was observed in inositol 1,4,5-triphosphate (IP3) type-2 receptor (R2) knock-out (KO) mice, in which the primary mechanism of astrocytic calcium increase-the release of calcium from intracellular stores following activation of an IP3-dependent pathway-is lacking. Further, our results in wild-type (WT) mice indicate that in vivo onset of astrocytic calcium increase in response to sensory stimulus could be considerably delayed relative to the simultaneously measured onset of arteriolar dilation. Delayed calcium increases in WT mice were observed in both astrocytic cell bodies and perivascular endfeet. Thus, astrocytes may not play a role in the initiation of blood flow response, at least not via calcium-dependent mechanisms. Moreover, an increase in astrocytic intracellular calcium was not required for normal vasodilation in the IP3R2-KO animals.
Recent advancements in radio frequency coils, field strength and sophisticated pulse sequences have propelled modern brain mapping and have made validation to biological standards - histology and pathology - possible. The medial temporal lobe has long been established as a pivotal brain region for connectivity, function and unique structure in the human brain, and reveals disconnection in mild Alzheimers disease. Specific brain mapping of mesocortical areas affected with neurofibrillary tangle pathology early in disease progression provides not only an accurate description for location of these areas but also supplies spherical coordinates that allow comparison between other ex vivo cases and larger in vivo datasets. We have identified several cytoarchitectonic features in the medial temporal lobe with high resolution ex vivo MRI, including gray matter structures such as the entorhinal layer II islands, perirhinal layer II-III columns, presubicular clouds, granule cell layer of the dentate gyrus as well as lamina of the hippocampus. Localization of Brodmann areas 28 and 35 (entorhinal and perirhinal, respectively) demonstrates MRI based area boundaries validated with multiple methods and histological stains. Based on our findings, both myelin and Nissl staining relate to contrast in ex vivo MRI. Precise brain mapping serves to create modern atlases for cortical areas, allowing accurate localization with important applications to detecting early disease processes.
Effective nasal continuous positive airway pressure (CPAP) therapy reduces the cardiovascular outcomes associated with obstructive sleep apnea (OSA), but the mechanism behind this effect is unclear. We investigated if OSA patients during wakefulness showed signs of increased sympathetic activity and decreased vasoreactivity in cerebral cortical vessels as measured with near-infrared spectroscopy (NIRS), and if this may be reversed by CPAP treatment.
This paper describes a novel optical method for label-free quantitative imaging of cerebral blood flow (CBF) and intracellular motility (IM) in the rodent cerebral cortex. This method is based on a technique that integrates dynamic light scattering (DLS) and optical coherence tomography (OCT), named DLS-OCT. The technique measures both the axial and transverse velocities of CBF, whereas conventional Doppler OCT measures only the axial one. In addition, the technique produces a three-dimensional map of the diffusion coefficient quantifying nontranslational motions. In the DLS-OCT diffusion map, we observed high-diffusion spots, whose locations highly correspond to neuronal cell bodies and whose diffusion coefficient agreed with that of the motion of intracellular organelles reported in vitro in the literature. Therefore, the present method has enabled, for the first time to our knowledge, label-free imaging of the diffusion-like motion of intracellular organelles in vivo. As an example application, we used the method to monitor CBF and IM during a brief ischemic stroke, where we observed an induced persistent reduction in IM despite the recovery of CBF after stroke. This result supports that the IM measured in this study represent the cellular energy metabolism-related active motion of intracellular organelles rather than free diffusion of intracellular macromolecules.
Behavioral studies have identified select experiences that can prime infants to attend to color information as the basis for individuating objects prior to the time they do so spontaneously. For example, viewing pretest events in which the color of an object predicts the function in which it will engage leads 9-month-olds (who typically do not attend to color differences) to demonstrate increased sensitivity to color information in a subsequent individuation task (Wilcox and Chapa, 2004). In contrast, viewing pretest events in which the color of an object predicts distinct object motions, but the motions are not functionally relevant, does not produce color priming. The purpose of the present research was to identify the cortical underpinnings of these behavioral effects. Infants aged 8 and 9months viewed function or motion pretest events and then their capacity to individuate-by-color was assessed in an object individuation task. Behavioral and neuroimaging data were collected. Two main findings emerged. First, as predicted, the infants who viewed the function but not the motion pretest events showed prolonged looking to the test event, a behavioral indicator of object individuation. In addition, they evidenced increased activation in anterior temporal cortex, thought to be a cortical signature of object individuation. A second and unexpected finding was that viewing either type of pretest events led to increased activation in the posterior temporal cortex, as compared to infants who did not see pretest events, revealing that prior exposure to the motion pretest events does influence infants processing of the test event, even though it is not evident in the behavioral results. The cognitive processes involved, and the cortical structures that mediate these processes, are discussed.
Visual working memory (VWM) is a core cognitive system with a highly limited capacity. The present study is the first to examine VWM capacity limits in early development using functional neuroimaging. We recorded optical neuroimaging data while 3- and 4-year-olds completed a change detection task where they detected changes in the shapes of objects after a brief delay. Near-infrared sources and detectors were placed over the following 10-20 positions: F3 and F5 in left frontal cortex, F4 and F6 in right frontal cortex, P3 and P5 in left parietal cortex, and P4 and P6 in right parietal cortex. The first question was whether we would see robust task-specific activation of the frontal-parietal network identified in the adult fMRI literature. This was indeed the case: three left frontal channels and 11 of 12 parietal channels showed a statistically robust difference between the concentration of oxygenated and deoxygenated hemoglobin following the presentation of the sample array. Moreover, four channels in the left hemisphere near P3, P5, and F5 showed a robust increase as the working memory load increased from 1 to 3 items. Notably, the hemodynamic response did not asymptote at 1-2 items as expected from previous fMRI studies with adults. Finally, 4-year-olds showed a more robust parietal response relative to 3-year-olds, and an increasing sensitivity to the memory load manipulation. These results demonstrate that fNIRS is an effective tool to study the neural processes that underlie the early development of VWM capacity.
As the applications of near-infrared spectroscopy (NIRS) continue to broaden and long-term clinical monitoring becomes more common, minimizing signal artifacts due to patient movement becomes more pressing. This is particularly true in applications where clinically and physiologically interesting events are intrinsically linked to patient movement, as is the case in the study of epileptic seizures. In this study, we apply an approach common in the application of EEG electrodes to the application of specialized NIRS optical fibers. The method provides improved optode-scalp coupling through the use of miniaturized optical fiber tips fixed to the scalp using collodion, a clinical adhesive. We investigate and quantify the performance of this new method in minimizing motion artifacts in healthy subjects, and apply the technique to allow continuous NIRS monitoring throughout epileptic seizures in two epileptic in-patients. Using collodion-fixed fibers reduces the percent signal change of motion artifacts by 90% and increases the SNR by 6 and 3 fold at 690 and 830nm wavelengths respectively when compared to a standard Velcro-based array of optical fibers. The SNR has also increased by 2 fold during rest conditions without motion with the new probe design because of better light coupling between the fiber and scalp. The change in both HbO and HbR during motion artifacts is found to be statistically lower for the collodion-fixed fiber probe. The collodion-fixed optical fiber approach has also allowed us to obtain good quality NIRS recording of three epileptic seizures in two patients despite excessive motion in each case.
Motion artifacts are a significant source of noise in many functional near-infrared spectroscopy (fNIRS) experiments. Despite this, there is no well-established method for their removal. Instead, functional trials of fNIRS data containing a motion artifact are often rejected completely. However, in most experimental circumstances the number of trials is limited, and multiple motion artifacts are common, particularly in challenging populations. Many methods have been proposed recently to correct for motion artifacts, including principle component analysis, spline interpolation, Kalman filtering, wavelet filtering and correlation-based signal improvement. The performance of different techniques has been often compared in simulations, but only rarely has it been assessed on real functional data. Here, we compare the performance of these motion correction techniques on real functional data acquired during a cognitive task, which required the participant to speak aloud, leading to a low-frequency, low-amplitude motion artifact that is correlated with the hemodynamic response. To compare the efficacy of these methods, objective metrics related to the physiology of the hemodynamic response have been derived. Our results show that it is always better to correct for motion artifacts than reject trials, and that wavelet filtering is the most effective approach to correcting this type of artifact, reducing the area under the curve where the artifact is present in 93% of the cases. Our results therefore support previous studies that have shown wavelet filtering to be the most promising and powerful technique for the correction of motion artifacts in fNIRS data. The analyses performed here can serve as a guide for others to objectively test the impact of different motion correction algorithms and therefore select the most appropriate for the analysis of their own fNIRS experiment.
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.
Minimally invasive, specific measurement of cellular energy metabolism is crucial for understanding cerebral pathophysiology. Here, we present high-resolution, in vivo observations of autofluorescence lifetime as a biomarker of cerebral energy metabolism in exposed rat cortices. We describe a customized two-photon imaging system with time correlated single photon counting detection and specialized software for modeling multiple-component fits of fluorescence decay and monitoring their transient behaviors. In vivo cerebral NADH fluorescence suggests the presence of four distinct components, which respond differently to brief periods of anoxia and likely indicate different enzymatic formulations. Individual components show potential as indicators of specific molecular pathways involved in oxidative metabolism.
The hemodynamic functional response is used as a reliable marker of neuronal activity in countless studies of brain function and cognition. In newborns and infants, however, conflicting results have appeared in the literature concerning the typical response, and there is little information on brain metabolism and functional activation. Measurement of all hemodynamic components and oxygen metabolism is critical for understanding neurovascular coupling in the developing brain. To this end, we combined multiple near infrared spectroscopy techniques to measure oxy- and deoxy-hemoglobin concentrations, cerebral blood volume (CBV), and relative cerebral blood flow (CBF) in the somatosensory cortex of 6 preterm neonates during passive tactile stimulation of the hand. By combining these measures we estimated relative changes in the cerebral metabolic rate of oxygen consumption (rCMRO2). CBF starts increasing immediately after stimulus onset, and returns to baseline before blood volume. This is consistent with the model of pre-capillary arteriole active dilation driving the CBF response, with a subsequent CBV increase influenced by capillaries and veins dilating passively to accommodate the extra blood. rCMRO2 estimated using the steady-state formulation shows a biphasic pattern: an increase immediately after stimulus onset, followed by a post-stimulus undershoot due to blood flow returning faster to baseline than oxygenation. However, assuming a longer mean transit time from the arterial to the venous compartment, due to the immature vascular system of premature infants, reduces the post-stimulus undershoot and increases the flow/consumption ratio to values closer to adult values reported in the literature. We are the first to report changes in local rCBF and rCMRO2 during functional activation in preterm infants. The ability to measure these variables in addition to hemoglobin concentration changes is critical for understanding neurovascular coupling in the developing brain, and for using this coupling as a reliable functional imaging marker in neonates.
Analysis of cerebral autoregulation by measuring spontaneous oscillations in the low frequency spectrum of cerebral cortical vessels might be a useful tool for assessing risk and investigating different treatment strategies in carotid artery disease and stroke. Near infrared spectroscopy (NIRS) is a non-invasive optical method to investigate regional changes in oxygenated (oxyHb) and deoxygenated hemoglobin (deoxyHb) in the outermost layers of the cerebral cortex. In the present study we examined oxyHb low frequency oscillations, believed to reflect cortical cerebral autoregulation, in 16 patients with both symptomatic carotid occlusive disease and cerebral hypoperfusion in comparison to healthy controls. Each hemisphere was examined with two NIRS channels using a 3?cm source detector distance. Arterial blood pressure (ABP) was measured via a finger plethysmograph. Using transfer function analysis ABP-oxyHb phase shift and gain as well as inter-hemispheric phase shift and amplitude ratio were assessed. We found that inter-hemispheric amplitude ratio was significantly altered in hypoperfusion patients compared to healthy controls (P?=?0.010), because of relatively lower amplitude on the hypoperfusion side. The inter-hemispheric phase shift showed a trend (P?=?0.061) toward increased phase shift in hypoperfusion patients compared to controls. We found no statistical difference between hemispheres in hypoperfusion patients for phase shift or gain values. There were no differences between the hypoperfusion side and controls for phase shift or gain values. These preliminary results suggest an impairment of autoregulation in hypoperfusion patients at the cortical level detected by NIRS.
Cardiac and respiratory motions in animals are the primary source of image quality degradation in dynamic imaging studies, especially when using phase-resolved imaging modalities such as spectral-domain optical coherence tomography (SD-OCT), whose phase signal is very sensitive to movements of the sample. This study demonstrates a method with which to compensate for motion artifacts in dynamic SD-OCT imaging of the rodent cerebral cortex. We observed that respiratory and cardiac motions mainly caused, respectively, bulk image shifts (BISs) and global phase fluctuations (GPFs). A cross-correlation maximization-based shift correction algorithm was effective in suppressing BISs, while GPFs were significantly reduced by removing axial and lateral global phase variations. In addition, a non-origin-centered GPF correction algorithm was examined. Several combinations of these algorithms were tested to find an optimized approach that improved image stability from 0.5 to 0.8 in terms of the cross-correlation over 4 s of dynamic imaging, and reduced phase noise by two orders of magnitude in ~8% voxels.
Quantification of nicotinamide adenine dinucleotide (NADH) changes during functional brain activation and pathological conditions provides critical insight into brain metabolism. Of the different imaging modalities, two-photon laser scanning microscopy (TPLSM) is becoming an important tool for cellular-resolution measurements of NADH changes associated with cellular metabolic changes. However, NADH fluorescence emission is strongly absorbed by hemoglobin. As a result, in vivo measurements are significantly affected by the hemodynamics associated with physiological and pathophysiological manipulations. We model NADH fluorescence excitation and emission in TPLSM imaging based on precise maps of cerebral microvasculature. The effects of hemoglobin optical absorption and optical scattering from red blood cells, changes in blood volume and hemoglobin oxygen saturation, vessel size, and location with respect to imaging location are explored. A simple technique for correcting the measured NADH fluorescence intensity changes is provided, with the utilization of a parallel measurement of a physiologically inert fluorophore. The model is applied to TPLSM measurements of NADH fluorescence intensity changes in rat somatosensory cortex during mild hypoxia and hyperoxia. The general approach of the correction algorithm can be extended to other TPLSM measurements, where changes in the optical properties of the tissue confound physiological measurements, such as the detection of calcium dynamics.
Cortical spreading depression (CSD) is associated with severe hypoperfusion in mice. Using minimally invasive multimodal optical imaging, we show that severe flow reductions during and after spreading depression are associated with a steep decline in cerebral metabolic rate of oxygen. Concurrent severe hemoglobin desaturation suggests that the oxygen metabolism becomes at least in part supply limited, and the decrease in cortical blood volume implicates vasoconstriction as the mechanism. In support of oxygen supply-demand mismatch, cortical nicotinamide adenine dinucleotide (NADH) fluorescence increases during spreading depression for at least 5?minutes, particularly away from parenchymal arterioles. However, modeling of tissue oxygen delivery shows that cerebral metabolic rate of oxygen drops more than predicted by a purely supply-limited model, raising the possibility of a concurrent reduction in oxygen demand during spreading depression. Importantly, a subsequent spreading depression triggered within 15?minutes evokes a monophasic flow increase superimposed on the oligemic baseline, which markedly differs from the response to the preceding spreading depression triggered in naive cortex. Altogether, these data suggest that CSD is associated with long-lasting oxygen supply-demand mismatch linked to severe vasoconstriction in mice.
Near-infrared spectroscopy measures of haemoglobin oxygen saturation are often used as an indicator of sufficient oxygen delivery to assess injury susceptibility and tissue damage. They have also often been used as a surrogate measure of oxygen metabolism. Unfortunately, these measures have generally failed to provide robust indicators of injury and metabolism. In this paper, we first review when haemoglobin oxygen saturation does work as a robust indicator, and then detail when and why it fails for assessing brain injury and breast cancer. Finally, we discuss the solution to obtain more robust measures of tissue injury and cancer by combining oxygen saturation measurements with measures of blood flow and volume to more accurately estimate oxygen metabolism.
In vivo imaging of cerebral tissue oxygenation is important in defining healthy physiology and pathological departures associated with cerebral disease. We used a recently developed two-photon microscopy method, based on a novel phosphorescent nanoprobe, to image tissue oxygenation in the rat primary sensory cortex in response to sensory stimulation. Our measurements showed that a stimulus-evoked increase in tissue pO? depended on the baseline pO? level. In particular, during sustained stimulation, the steady-state pO? at low-baseline locations remained at the baseline, despite large pO? increases elsewhere. In contrast to the steady state, where pO? never decreased below the baseline, transient decreases occurred during the "initial dip" and "poststimulus undershoot." These results suggest that the increase in blood oxygenation during the hemodynamic response, which has been perceived as a paradox, may serve to prevent a sustained oxygenation drop at tissue locations that are remote from the vascular feeding sources.
Near-Infrared Spectroscopy (NIRS) measures the functional hemodynamic response occurring 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 (?HbR) is equal to 16-22% of the cortical contribution to the total hemoglobin signal change (?HbT). Similarly, the cortical contribution of the oxyhemoglobin signal change (?HbO) is equal to 73-79% of the cortical contribution to the ?HbT signal. These results suggest that ?HbT is far less sensitive to pial vein contamination and therefore, it is likely that the ?HbT signal provides better spatial specificity and should be used instead of ?HbO or ?HbR 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.
Near-infrared spectroscopy (NIRS) signals have been shown to correlate with resting-state BOLD-fMRI data across the whole brain volume, particularly at frequencies below 0.1Hz. While the physiological origins of this correlation remain unclear, its existence may have a practical application in minimizing the background physiological noise present in BOLD-fMRI recordings. We performed simultaneous, resting-state fMRI and 28-channel NIRS in seven adult subjects in order to assess the utility of NIRS signals in the regression of physiological noise from fMRI data. We calculated the variance of the residual error in a general linear model of the baseline fMRI signal, and the reduction of this variance achieved by including NIRS signals in the model. In addition, we introduced a sequence of simulated hemodynamic response functions (HRFs) into the resting-state fMRI data of each subject in order to quantify the effectiveness of NIRS signals in optimizing the recovery of that HRF. For comparison, these calculations were also performed using a pulse and respiration RETROICOR model. Our results show that the use of 10 or more NIRS channels can reduce variance in the residual error by as much as 36% on average across the whole cortex. However the same number of low-pass filtered white noise regressors is shown to produce a reduction of 19%. The RETROICOR model obtained a variance reduction of 6.4%. Our HRF simulation showed that the mean-squared error (MSE) between the recovered and true HRFs is reduced by 21% on average when 10 NIRS channels are applied and by introducing an optimized time lag between the NIRS and fMRI time series, a single NIRS channel can provide an average MSE reduction of 14%. The RETROICOR model did not provide a significant change in MSE. By each of the metrics calculated, NIRS recording is shown to be of significant benefit to the regression of low-frequency physiological noise from fMRI data.
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.
Even though cellular volume dynamics has been linked to cell apoptosis and intrinsic optical signals, there is no quantitative model for describing neuronal volume dynamics on the millisecond time scale. This study introduces a multiphysics neuron model, where the cell volume is a time-varying variable and multiple physical principles are combined to build governing equations. Using this model, we analyzed neuronal volume responses during excitation, which elucidated the variety of optical signals observed experimentally across the literature. Several physiological conditions were examined to investigate their effect on the pattern of volume response. In addition, we analyzed volume responses on a longer time scale with repetitive stimulation to study the characteristics of slow cell swelling. This multiscale analysis of the multiphysics model will provide not only a novel quantitative elucidation of physiologically important issues related with cellular volume dynamics but also a chance for further studies, such as the interesting possibility of inferring the balance of ion flux from plateau volume changes.
Monitoring of the spatiotemporal characteristics of cerebral blood and tissue oxygenation is crucial for better understanding of the neuro-metabolic-vascular relationship. Development of new pO2 measurement modalities with simultaneous monitoring of pO2 in larger fields of view with higher spatial and/or temporal resolution will enable greater insight into the functioning of the normal brain and will also have significant impact on diagnosis and treatment of neurovascular diseases such as stroke, Alzheimers disease, and head injury. Optical imaging modalities have shown a great potential to provide high spatiotemporal resolution and quantitative imaging of pO2 based on hemoglobin absorption in visible and near infrared range of optical spectrum. However, multispectral measurement of cerebral blood oxygenation relies on photon migration through the highly scattering brain tissue. Estimation and modeling of tissue optical parameters, which may undergo dynamic changes during the experiment, is typically required for accurate estimation of blood oxygenation. On the other hand, estimation of the partial pressure of oxygen (pO2) based on oxygen-dependent quenching of phosphorescence should not be significantly affected by the changes in the optical parameters of the tissue and provides an absolute measure of pO2. Experimental systems that utilize oxygen-sensitive dyes have been demonstrated in in vivo studies of the perfused tissue as well as for monitoring the oxygen content in tissue cultures, showing that phosphorescence quenching is a potent technology capable of accurate oxygen imaging in the physiological pO2 range. Here we demonstrate with two different imaging modalities how to perform measurement of pO2 in cortical vasculature based on phosphorescence lifetime imaging. In first demonstration we present wide field of view imaging of pO2 at the cortical surface of a rat. This imaging modality has relatively simple experimental setup based on a CCD camera and a pulsed green laser. An example of monitoring the cortical spreading depression based on phosphorescence lifetime of Oxyphor R3 dye was presented. In second demonstration we present a high resolution two-photon pO2 imaging in cortical micro vasculature of a mouse. The experimental setup includes a custom built 2-photon microscope with femtosecond laser, electro-optic modulator, and photon-counting photo multiplier tube. We present an example of imaging the pO2 heterogeneity in the cortical microvasculature including capillaries, using a novel PtP-C343 dye with enhanced 2-photon excitation cross section.
We suggest that Diffuse Correlation Spectroscopy (DCS) measurements of tissue blood flow primarily probe relative red blood cell (RBC) motion, due to the occurrence of multiple sequential scattering events within blood vessels. The magnitude of RBC shear-induced diffusion is known to correlate with flow velocity, explaining previous reports of linear scaling of the DCS "blood flow index" with tissue perfusion despite the observed diffusion-like auto-correlation decay. Further, by modeling RBC mean square displacement using a formulation that captures the transition from ballistic to diffusive motion, we improve the fit to experimental data and recover effective diffusion coefficients and velocity de-correlation time scales in the range expected from previous blood rheology studies.
Laser Speckle Imaging (LSI) images interference patterns produced by coherent addition of scattered laser light to map subsurface tissue perfusion. However, the effect of longer path length photons is typically unknown and poses a limitation towards absolute quantification. In this work, LSI is integrated with spatial frequency domain imaging (SFDI) to suppress multiple scattering and absorption effects. First, depth sensitive speckle contrast is shown in phantoms by separating a deep source (4 mm) from a shallow source (2 mm) of speckle contrast by using a high spatial frequency of illumination (0.24 mm(-1)). We develop an SFD adapted correlation diffusion model and show that with high frequency (0.24 mm(-1)) illumination, doubling of absorption contrast results in only a 1% change in speckle contrast versus 25% change using a planar unmodulated (0 mm(-1)) illumination. Similar absorption change is mimicked in vivo imaging a finger occlusion and the relative speckle contrast change from baseline is 10% at 0.26 mm(-1) versus 60% at 0 mm(-1) during a finger occlusion. These results underscore the importance of path length and optical properties in determining speckle contrast. They provide an integrated approach for simultaneous mapping of blood flow (speckle contrast) and oxygenation (optical properties) which can be used to inform tissue metabolism.
Doppler optical coherence tomography (DOCT) and OCT angiography are novel methods to investigate cerebrovascular physiology. In the rodent cortex, DOCT flow displays features characteristic of cerebral blood flow, including conservation along nonbranching vascular segments and at branch points. Moreover, DOCT flow values correlate with hydrogen clearance flow values when both are measured simultaneously. These data validate DOCT as a noninvasive quantitative method to measure tissue perfusion over a physiologic range.
Diffuse optical imaging (DOI) allows the recovery of the hemodynamic response associated with evoked brain activity. The signal is contaminated with systemic physiological interference which occurs in the superficial layers of the head as well as in the brain tissue. The back-reflection geometry of the measurement makes the DOI signal strongly contaminated by systemic interference occurring in the superficial layers. A recent development has been the use of signals from small source-detector separation (1cm) optodes as regressors. Since those additional measurements are mainly sensitive to superficial layers in adult humans, they help in removing the systemic interference present in longer separation measurements (3 cm). Encouraged by those findings, we developed a dynamic estimation procedure to remove global interference using small optode separations and to estimate simultaneously the hemodynamic response. The algorithm was tested by recovering a simulated synthetic hemodynamic response added over baseline DOI data acquired from 6 human subjects at rest. The performance of the algorithm was quantified by the Pearson R(2) coefficient and the mean square error (MSE) between the recovered and the simulated hemodynamic responses. Our dynamic estimator was also compared with a static estimator and the traditional adaptive filtering method. We observed a significant improvement (two-tailed paired t-test, p<0.05) in both HbO and HbR recovery using our Kalman filter dynamic estimator compared to the traditional adaptive filter, the static estimator and the standard GLM technique.
The near infrared spectroscopy (NIRS) frequency-domain multi-distance (FD-MD) method allows for the estimation of optical properties in biological tissue using the phase and intensity of radiofrequency modulated light at different source-detector separations. In this study, we evaluated the accuracy of this method to retrieve the absorption coefficient of the brain at different ages. Synthetic measurements were generated with Monte Carlo simulations in magnetic resonance imaging (MRI)-based heterogeneous head models for four ages: newborn, 6 and 12 month old infants, and adult. For each age, we determined the optimal set of source-detector separations and estimated the corresponding errors. Errors arise from different origins: methodological (FD-MD) and anatomical (curvature, head size and contamination by extra-cerebral tissues). We found that the brain optical absorption could be retrieved with an error between 8-24% in neonates and infants, while the error increased to 19-44% in adults over all source-detector distances. The dominant contribution to the error was found to be the head curvature in neonates and infants, and the extra-cerebral tissues in adults.
Absorption or fluorescence-based two-dimensional (2-D) optical imaging is widely employed in functional brain imaging. The image is a weighted sum of the real signal from the tissue at different depths. This weighting function is defined as "depth sensitivity." Characterizing depth sensitivity and spatial resolution is important to better interpret the functional imaging data. However, due to light scattering and absorption in biological tissues, our knowledge of these is incomplete. We use Monte Carlo simulations to carry out a systematic study of spatial resolution and depth sensitivity for 2-D optical imaging methods with configurations typically encountered in functional brain imaging. We found the following: (i) the spatial resolution is <200 ?m for NA?0.2 or focal plane depth?300 ?m. (ii) More than 97% of the signal comes from the top 500 ?m of the tissue. (iii) For activated columns with lateral size larger than spatial resolution, changing numerical aperature (NA) and focal plane depth does not affect depth sensitivity. (iv) For either smaller columns or large columns covered by surface vessels, increasing NA and/or focal plane depth may improve depth sensitivity at deeper layers. Our results provide valuable guidance for the optimization of optical imaging systems and data interpretation.
Measuring cerebral oxygen delivery and metabolism microscopically is important for interpreting macroscopic functional magnetic resonance imaging (fMRI) data and identifying pathological changes associated with stroke, Alzheimers disease, and brain injury. Here, we present simultaneous, microscopic measurements of cerebral blood flow (CBF) and oxygen partial pressure (pO(2)) in cortical microvessels of anesthetized rats under baseline conditions and during somatosensory stimulation. Using a custom-built imaging system, we measured CBF with Fourier-domain optical coherence tomography (OCT), and vascular pO(2) with confocal phosphorescence lifetime microscopy. Cerebral blood flow and pO(2) measurements displayed heterogeneity over distances irresolvable with fMRI and positron emission tomography. Baseline measurements indicate O(2) extraction from pial arterioles and homogeneity of ascending venule pO(2) despite large variation in microvessel flows. Oxygen extraction is linearly related to flow in ascending venules, suggesting that flow in ascending venules closely matches oxygen demand of the drained territory. Oxygen partial pressure and relative CBF transients during somatosensory stimulation further indicate arteriolar O(2) extraction and suggest that arterioles contribute to the fMRI blood oxygen level dependent response. Understanding O(2) supply on a microscopic level will yield better insight into brain function and the underlying mechanisms of various neuropathologies.
Fundamental to the interpretation of neurovascular coupling is determining the neuronal activity that accounts for functional hyperemia. Recently, synaptic and not spiking activity has been found to be responsible for the hemodynamic response. Using pharmacological manipulation in rats, we want to further determine whether the cortical synaptic activity generated by the thalamic input or the subsequent synaptic activity related to secondary cortical processing is driving the hemodynamic response. In this study, we topically applied ?-aminobutyric acid (GABA) in the somatosensory cortex and used electrical forepaw stimulation to evoke neural and vascular activity. In a group of 8 animals, using laminar electrophysiology, we verified that topical application of GABA for 20min does not affect layer IV synaptic activity but reduces subsequent activity in the supragranular and infragranular layers. In another group of 8 animals, we simultaneously measured the electrical and vascular responses with scalp electroencephalography (EEG) and diffuse optical imaging (DOI), respectively. We decomposed somatosensory evoked potentials (SEP) into three major components: P1, N1, and P2, where P1 represents the thalamic input activity originating in layer IV and N1 and P2 represent the subsequent cortical transmissions. We verified that GABA infusion in the somatosensory cortex does not significantly reduce the P1 SEP component but strongly reduces the N1 and P2 components. We found that GABA also elicits a large reduction in the hemodynamic responses, which correlate with the reduction in N1 and P2 components. These results suggest that the hemodynamic response is predominantly driven by cortico-cortical interactions and not by the initial thalamocortical activity in layer IV.
The etiology behind and physiological significance of spontaneous oscillations in the low-frequency spectrum in both systemic and cerebral vessels remain unknown. Experimental studies have proposed that spontaneous oscillations in cerebral blood flow reflect impaired cerebral autoregulation (CA). Analysis of CA by measurement of spontaneous oscillations in the low-frequency spectrum in cerebral vessels might be a useful tool for assessing risk and investigating different treatment strategies in carotid artery disease (CAD) and stroke. We reviewed studies exploring spontaneous oscillations in the low-frequency spectrum in patients with CAD and ischemic stroke, conditions known to involve impaired CA. Several studies have reported changes in oscillations after CAD and stroke after surgery and over time compared with healthy controls. Phase shift in the frequency domain and correlation coefficients in the time domain are the most frequently used parameters for analyzing spontaneous oscillations in systemic and cerebral vessels. At present, there is no gold standard for analyzing spontaneous oscillations in the low-frequency spectrum, and simplistic models of CA have failed to predict or explain the spontaneous oscillation changes found in CAD and stroke studies. Near-infrared spectroscopy is suggested as a future complementary tool for assessing changes affecting the cortical arterial system.
Near-infrared (NIR) fluorescence tomography of multiple fluorophores has previously been limited by the bandwidth of the NIR spectral regime and the broad emission spectra of most NIR fluorophores. We describe in vivo tomography of three spectrally overlapping fluorophores using fluorescence lifetime-based separation. Time-domain images are acquired using a voltage-gated, intensified charge-coupled device (CCD) in free-space transmission geometry with 750 nm Ti:sapphire laser excitation. Lifetime components are fit from the asymptotic portion of fluorescence decay curve and reconstructed separately with a lifetime-adjusted forward model. We use this system to test the in vivo lifetime multiplexing suitability of commercially available fluorophores, and demonstrate lifetime multiplexing in solution mixtures and in nude mice. All of the fluorophores tested exhibit nearly monoexponential decays, with narrow in vivo lifetime distributions suitable for lifetime multiplexing. Quantitative separation of two fluorophores with lifetimes of 1.1 and 1.37 ns is demonstrated for relative concentrations of 1:5. Finally, we demonstrate tomographic imaging of two and three fluorophores in nude mice with fluorophores that localize to distinct organ systems. This technique should be widely applicable to imaging multiple NIR fluorophores in 3-D.
Changes in neuronal activity are accompanied by the release of vasoactive mediators that cause microscopic dilation and constriction of the cerebral microvasculature and are manifested in macroscopic blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals. We used two-photon microscopy to measure the diameters of single arterioles and capillaries at different depths within the rat primary somatosensory cortex. These measurements were compared with cortical depth-resolved fMRI signal changes. Our microscopic results demonstrate a spatial gradient of dilation onset and peak times consistent with "upstream" propagation of vasodilation toward the cortical surface along the diving arterioles and "downstream" propagation into local capillary beds. The observed BOLD response exhibited the fastest onset in deep layers, and the "initial dip" was most pronounced in layer I. The present results indicate that both the onset of the BOLD response and the initial dip depend on cortical depth and can be explained, at least in part, by the spatial gradient of delays in microvascular dilation, the fastest response being in the deep layers and the most delayed response in the capillary bed of layer I.
We describe methods and algorithms for rapid volumetric imaging of cortical vasculature with optical coherence tomography (OCT). By optimizing system design, scanning protocols, and algorithms for visualization of capillary flow, comprehensive imaging of the surface pial vasculature and capillary bed is performed in approximately 12 s. By imaging during hypercapnia and comparing with simultaneous CCD imaging, the sources of contrast of OCT angiography are investigated.
Measurements of oxygen partial pressure (pO(2)) with high temporal and spatial resolution in three dimensions is crucial for understanding oxygen delivery and consumption in normal and diseased brain. Among existing pO(2) measurement methods, phosphorescence quenching is optimally suited for the task. However, previous attempts to couple phosphorescence with two-photon laser scanning microscopy have faced substantial difficulties because of extremely low two-photon absorption cross-sections of conventional phosphorescent probes. Here we report to our knowledge the first practical in vivo two-photon high-resolution pO(2) measurements in small rodents cortical microvasculature and tissue, made possible by combining an optimized imaging system with a two-photon-enhanced phosphorescent nanoprobe. The method features a measurement depth of up to 250 microm, sub-second temporal resolution and requires low probe concentration. The properties of the probe allowed for direct high-resolution measurement of cortical extravascular (tissue) pO(2), opening many possibilities for functional metabolic brain studies.
The development of effective multi-modality imaging methods typically requires an efficient information fusion model, particularly when combining structural images with a complementary imaging modality that provides functional information. We propose a composition-based image segmentation method for X-ray digital breast tomosynthesis (DBT) and a structural-prior-guided image reconstruction for a combined DBT and diffuse optical tomography (DOT) breast imaging system. Using the 3D DBT images from 31 clinically measured healthy breasts, we create an empirical relationship between the X-ray intensities for adipose and fibroglandular tissue. We use this relationship to then segment another 58 healthy breast DBT images from 29 subjects into compositional maps of different tissue types. For each breast, we build a weighted-graph in the compositional space and construct a regularization matrix to incorporate the structural priors into a finite-element-based DOT image reconstruction. Use of the compositional priors enables us to fuse tissue anatomy into optical images with less restriction than when using a binary segmentation. This allows us to recover the image contrast captured by DOT but not by DBT. We show that it is possible to fine-tune the strength of the structural priors by changing a single regularization parameter. By estimating the optical properties for adipose and fibroglandular tissue using the proposed algorithm, we found the results are comparable or superior to those estimated with expert-segmentations, but does not involve the time-consuming manual selection of regions-of-interest.
Resting state connectivity aims to identify spontaneous cerebral hemodynamic fluctuations that reflect neuronal activity at rest. In this study, we investigated the spatial-temporal correlation of hemoglobin concentration signals over the whole head during the resting state. By choosing a source-detector pair as a seed, we calculated the correlation value between its time course and the time course of all other source-detector combinations, and projected them onto a topographic map. In all subjects, we found robust spatial interactions in agreement with previous fMRI and NIRS findings. Strong correlations between the two opposite hemispheres were seen for both sensorimotor and visual cortices. Correlations in the prefrontal cortex were more heterogeneous and dependent on the hemodynamic contrast. HbT provided robust, well defined maps, suggesting that this contrast may be used to better localize functional connectivity. The effects of global systemic physiology were also investigated, particularly low frequency blood pressure oscillations which give rise to broad regions of high correlation and mislead interpretation of the results. These results confirm the feasibility of using functional connectivity with optical methods during the resting state, and validate its use to investigate cortical interactions across the whole head.
Phonological density refers to the number of words that can be generated by replacing a phoneme in a target word with another phoneme in the same position. Although the precise nature of the phonological neighborhood density effect is not firmly established, many behavioral psycholinguistic studies have shown that visual recognition of individual words is influenced by the number and type of neighbors the words have. This study explored neurobehavioral correlates of phonological neighborhood density in skilled readers of English using near infrared spectroscopy. On the basis of a lexical decision task, our findings showed that words with many phonological neighbors (e.g., FRUIT) were recognized more slowly than words with few phonological neighbors (e.g., PROOF), and that words with many neighbors elicited significantly greater changes in blood oxygenation in the left than in the right hemisphere of the brain, specifically in the areas BA 22/39/40. In previous studies these brain areas have been implicated in fine-grained phonological processing in readers of English. The present findings provide the first demonstration that areas BA 22/39/40 are also sensitive to phonological density effects.
Bilateral regions of the intraparietal sulcus (IPS) appear to be functionally selective for both rudimentary non-symbolic number tasks and higher-level symbolic number tasks in adults and older children. Furthermore, the ability to mentally represent and manipulate approximate non-symbolic numerical quantities is present from birth. These factors leave open whether the specialization of the IPS develops through the experience of learning a symbolic number system or if it is already specialized before symbolic number acquisition. Using the newly emerging technique of functional Near-Infrared Spectroscopy (fNIRS) over left and right parietal and lateral occipital regions, we show right parietal specialization for number in 6-month-old infants. These results extend the current literature in three ways: by successfully implementing an event-related NIRS design in infants, by showing parietal specialization for number occurs before the acquisition of language, and by suggesting number representation may be initially right lateralized and becomes bilateral through experience.
First introduced in the 1980s, laser speckle contrast imaging is a powerful tool for full-field imaging of blood flow. Recently laser speckle contrast imaging has gained increased attention, in part due to its rapid adoption for blood flow studies in the brain. We review the underlying physics of speckle contrast imaging and discuss recent developments to improve the quantitative accuracy of blood flow measures. We also review applications of laser speckle contrast imaging in neuroscience, dermatology and ophthalmology.
To date, the majority of neurovascular coupling studies focused on the thalamic afferents activity in layer IV and the corresponding large spiking activity as responsible for functional hyperemia. This paper highlights the role of the secondary and late cortico-cortical transmission in neurovascular coupling. Simultaneous scalp electroencephalography (EEG) and diffuse optical imaging (DOI) measurements were obtained during multiple conditions of event-related electrical forepaw stimulation in 33 male Sprague-Dawley rats divided into 6 groups depending on the maintaining anesthetic - alpha-chloralose, pentobarbital, ketamine-xylazine, fentanyl-droperidol, isoflurane, or propofol. The somatosensory evoked potentials (SEP) were decomposed into four components and the question of which best predicts the hemodynamic responses was investigated. Results of the linear regression analysis show that the hemodynamic response is best correlated with the secondary and late cortico-cortical transmissions and not with the initial thalamic input activity in layer IV. Baseline cerebral blood flow (CBF) interacts with neural activity and influences the evoked hemodynamic responses. Finally, neurovascular coupling appears to be the same across all anesthetics used.
Absolute measurements of cerebral blood flow (CBF) are an important endpoint in studies of cerebral pathophysiology. Currently no accepted method exists for in vivo longitudinal monitoring of CBF with high resolution in rats and mice. Using three-dimensional Doppler Optical Coherence Tomography and cranial window preparations, we present methods and algorithms for regional CBF measurements in the rat cortex. Towards this end, we develop and validate a quantitative statistical model to describe the effect of static tissue on velocity sensitivity. This model is used to design scanning protocols and algorithms for sensitive 3D flow measurements and angiography of the cortex. We also introduce a method of absolute flow calculation that does not require explicit knowledge of vessel angles. We show that OCT estimates of absolute CBF values in rats agree with prior measures by autoradiography, suggesting that Doppler OCT can perform absolute flow measurements in animal models.
Spreading depression (SD) is a slowly propagating wave of transient neuronal and glial depolarization that develops after stroke, trauma and subarachnoid hemorrhage. In compromised tissue, repetitive SD-like injury depolarizations reduce tissue viability by worsening the mismatch between blood flow and metabolism. Although the mechanism remains unknown, SDs show delayed electrophysiological recovery within the ischemic penumbra. Here, we tested the hypothesis that the recovery rate of SD can be varied by modulating tissue perfusion pressure and oxygenation. Systemic blood pressure and arterial pO(2) were simultaneously manipulated in anesthetized rats under full physiologic monitoring. We found that arterial hypotension doubled the SD duration, whereas hypertension reduced it by a third compared with normoxic normotensive rats. Hyperoxia failed to shorten the prolonged SD durations in hypotensive rats, despite restoring tissue pO(2). Indeed, varying arterial pO(2) (40 to 400 mm Hg) alone did not significantly influence SD duration, whereas blood pressure (40 to 160 mm Hg) was inversely related to SD duration in compromised tissue. These data suggest that cerebral perfusion pressure is a critical determinant of SD duration independent of tissue oxygenation over a wide range of arterial pO(2) levels, and that hypotension may be detrimental in stroke and subarachnoid hemorrhage, where SD-like injury depolarizations have been observed.
A great deal is known about the development of visual object processing capacities and the neural structures that mediate these capacities in the mature observer. In contrast, little is known about the neural structures that mediate these capacities in the infant or how these structures eventually give rise to mature processing. The present research used near-infrared spectroscopy to investigate neural activation in visual, temporal, and parietal cortex during object processing tasks. Infants aged 5-7 months viewed visual events that required processing of the featural (Experiment 1) or the spatiotemporal (Experiment 2) properties of objects. In Experiment 1, different patterns of neural were obtained in temporal cortex in response to shape than color information. In Experiment 2, different patterns of neural activation were obtained in parietal cortex in response to spatiotemporal (speed and path of motion) than featural (shape and color) information. These results suggest a dissociation of processing of featural and spatiotemporal information in the infant cortex and provide evidence for early functional specification of the human brain. The outcome of these studies informs brain-behavior models of cognitive development and lays the foundation for systematic investigation of the functional maturation of object processing systems in the infant brain.
We report a parallel Monte Carlo algorithm accelerated by graphics processing units (GPU) for modeling time-resolved photon migration in arbitrary 3D turbid media. By taking advantage of the massively parallel threads and low-memory latency, this algorithm allows many photons to be simulated simultaneously in a GPU. To further improve the computational efficiency, we explored two parallel random number generators (RNG), including a floating-point-only RNG based on a chaotic lattice. An efficient scheme for boundary reflection was implemented, along with the functions for time-resolved imaging. For a homogeneous semi-infinite medium, good agreement was observed between the simulation output and the analytical solution from the diffusion theory. The code was implemented with CUDA programming language, and benchmarked under various parameters, such as thread number, selection of RNG and memory access pattern. With a low-cost graphics card, this algorithm has demonstrated an acceleration ratio above 300 when using 1792 parallel threads over conventional CPU computation. The acceleration ratio drops to 75 when using atomic operations. These results render the GPU-based Monte Carlo simulation a practical solution for data analysis in a wide range of diffuse optical imaging applications, such as human brain or small-animal imaging.
We describe depth-resolved microscopy of cortical hemodynamics with high-speed spectral/Fourier domain optical coherence tomography (OCT). Stimulus-evoked changes in blood vessel diameter, flow, and total hemoglobin were measured in the rat somatosensory cortex. The results show OCT measurements of hemodynamic changes during functional activation and represent an important step toward understanding functional hyperemia at the microscopic level.
The relationship between cerebral blood volume (CBV) and blood flow (CBF) has gained widespread interest because of its utility in using functional magnetic resonance imaging and optical imaging methods to estimate the cerebral metabolic rate of oxygen (CMRO(2)). A recent paper by Leung et al (2009 Physiol. Meas. 30 1-12) nicely presents measurements relating CBV to cerebral blood flow velocity (CBFV) as measured by near infrared spectroscopy and transcranial Doppler, respectively. They suggest that this relationship cannot be inverted to estimate CBF (or CBFV) from CBV, and that doing so to estimate CMRO(2) is inappropriate. We argue that these data, and other related published data, do permit the estimation of CBF from CBV and thus enable CMRO(2) to be estimated when only measures of CBV and deoxygenated hemoglobin are available.
The relationship between measurements of cerebral blood oxygenation and neuronal activity is highly complex and depends on both neurovascular and neurometabolic biological coupling. While measurements of blood oxygenation changes via optical and MRI techniques have been developed to map functional brain activity, there is evidence that the specific characteristics of these signals are sensitive to the underlying vascular physiology and structure of the brain. Since baseline blood flow and oxygen saturation may vary between sessions and across subjects, functional blood oxygenation changes may be a less reliable indicator of brain activity in comparison to blood flow and metabolic changes. In this work, we use a biomechanical model to examine the relationships between neural, vascular, metabolic, and hemodynamic responses to parametric whisker stimulation under both normal and hypercapnic conditions in a rat model. We find that the relationship between neural activity and oxy- and deoxyhemoglobin changes is sensitive to hypercapnia-induced changes in baseline cerebral blood flow. In contrast, the underlying relationships between evoked neural activity, blood flow, and model-estimated oxygen metabolism changes are unchanged by the hypercapnic challenge. We conclude that evoked changes in blood flow and cerebral oxygen metabolism are more closely associated with underlying evoked neuronal responses.
Oxygen levels in biological systems can be measured by the phosphorescence quenching method using probes with controllable quenching parameters and defined biodistributions. We describe a general approach to the construction of phosphorescent nanosensors with tunable spectral characteristics, variable degrees of quenching, and a high selectivity for oxygen. The probes are based on bright phosphorescent Pt and Pd complexes of porphyrins and symmetrically pi-extended porphyrins (tetrabenzoporphyrins and tetranaphthoporphyrins). pi-Extension of the core macrocycle allows tuning of the spectral parameters of the probes in order to meet the requirements of a particular imaging application (e.g., oxygen tomography versus planar microscopic imaging). Metalloporphyrins are encapsulated into poly(arylglycine) dendrimers, which fold in aqueous environments and create diffusion barriers for oxygen, making it possible to regulate the sensitivity and the dynamic range of the method. The periphery of the dendrimers is modified with poly(ethylene glycol) residues, which enhance the probes solubility, diminish toxicity, and help prevent interactions of the probes with the biological environment. The probes parameters were measured under physiological conditions and shown to be unaffected by the presence of biomacromolecules. The performance of the probes was demonstrated in applications, including in vivo microscopy of vascular pO(2) in the rat brain.
Pain is difficult to assess due to the subjective nature of self-reporting. The lack of objective measures of pain has hampered the development of new treatments as well as the evaluation of current ones. Functional MRI studies of pain have begun to delineate potential brain response signatures that could be used as objective read-outs of pain. Using Diffuse Optical Tomography (DOT), we have shown in the past a distinct DOT signal over the somatosensory cortex to a noxious heat stimulus that could be distinguished from the signal elicited by innocuous mechanical stimuli. Here we further our findings by studying the response to thermal innocuous and noxious stimuli.
With the increasing interest in treatments for neonatal brain injury, bedside methods for detecting and assessing injury status and evolution are needed. We aimed to determine whether cerebral tissue oxygenation (StO(2)), cerebral blood volume (CBV), and estimates of relative cerebral oxygen consumption (rCMRO(2)) determined by bedside frequency-domain near-infrared spectroscopy (FD-NIRS) have the potential to distinguish neonates with brain injury from those with non-brain issues and healthy controls. We recruited 43 neonates < or =15 days old and >33 weeks gestational age (GA): 14 with imaging evidence of brain injury, 29 without suspicion of brain injury (4 unstable, 6 stable, and 19 healthy). A multivariate analysis of variance with Newman-Keuls post hoc comparisons confirmed group similarity for GA and age at measurement. StO(2) was significantly higher in brain injured compared with unstable neonates, but not statistically different from stable or healthy neonates. Brain-injured neonates were distinguished from all others by significant increases in CBV and rCMRO(2). In conclusion, although NIRS measures of StO(2) alone may be insensitive to evolving brain injury, increased CBV and rCMRO(2) seem to be useful for detecting neonatal brain injury and suggest increased neuronal activity and metabolism occurs acutely in evolving brain injury.
We show that fluorescence lifetime is a powerful contrast mechanism that can enhance the whole-body imaging of fluorescent proteins (FPs), in the presence of background tissue autofluorescence (AF). The nonexponential AF decay is characterized from time-domain (TD) measurements on multiple nude mice and separated from the FP fluorescence using a linear fit to a priori basis functions. We illustrate this approach using an orthotopic mouse tumor model of breast adenocarcinoma. We also report that four commonly used FPs show distinct lifetimes, indicating their suitability for in vivo lifetime multiplexing. These results suggest the potential for exploiting fluorescence lifetime for imaging FPs for a variety of whole-body small-animal imaging applications.
Stimulus evoked changes in cerebral blood flow, volume, and oxygenation arise from responses to underlying neuronally mediated changes in vascular tone and cerebral oxygen metabolism. There is increasing evidence that the magnitude and temporal characteristics of these evoked hemodynamic changes are additionally influenced by the local properties of the vasculature including the levels of baseline cerebral blood flow, volume, and blood oxygenation. In this work, we utilize a physiologically motivated vascular model to describe the temporal characteristics of evoked hemodynamic responses and their expected relationships to the structural and biomechanical properties of the underlying vasculature. We use this model in a temporal curve-fitting analysis of the high-temporal resolution functional MRI data to estimate the underlying cerebral vascular and metabolic responses in the brain. We present evidence for the feasibility of our model-based analysis to estimate transient changes in the cerebral metabolic rate of oxygen (CMRO(2)) in the human motor cortex from combined pulsed arterial spin labeling (ASL) and blood oxygen level dependent (BOLD) MRI. We examine both the numerical characteristics of this model and present experimental evidence to support this model by examining concurrently measured ASL, BOLD, and near-infrared spectroscopy to validate the calculated changes in underlying CMRO(2).
Comprehending the underlying mechanisms of neurovascular coupling is important for understanding the pathogenesis of neurodegenerative diseases related to uncoupling. Moreover, it elucidates the casual relation between the neural signaling and the hemodynamic responses measured with various imaging modalities such as functional magnetic resonance imaging (fMRI). There are mainly two hypotheses concerning this mechanism: a metabolic hypothesis and a neurogenic hypothesis. We have modified recent models of neurovascular coupling adding the effects of both NO (nitric oxide) kinetics, which is a well-known neurogenic vasodilator, and CO(2) kinetics as a metabolic vasodilator. We have also added the Hodgkin-Huxley equations relating the membrane potentials to sodium influx through the membrane. Our results show that the dominant factor in the hemodynamic response is NO, however CO(2) is important in producing a brief post-stimulus undershoot in the blood flow response that in turn modifies the fMRI blood oxygenation level-dependent post-stimulus undershoot. Our results suggest that increased cerebral blood flow during stimulation causes CO(2) washout which then results in a post-stimulus hypocapnia induced vasoconstrictive effect.
Over the last 20 years neuroscientists have learned a great deal about the ventral and dorsal object processing pathways in the adult brain, yet little is known about the functional development of these pathways. The present research assessed the extent to which different patterns of neural activation, as measured by changes in blood volume and oxygenation, are observed in infant visual and temporal cortex in response to events that involve processing of featural differences or spatiotemporal discontinuities. Infants aged 6.5 months were tested. Increased neural activation was observed in visual cortex in response to a featural-difference and a spatiotemporal-discontinuity event. In addition, increased neural activation was observed in temporal cortex in response to the featural-difference but not the spatiotemporal-discontinuity event. The outcome of this experiment reveals early functional specialization of temporal cortex and lays the foundation for future investigation of the maturation of object processing pathways in humans.
Functional neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS) can be used to isolate an evoked response to a stimulus from significant background physiological fluctuations. Data analysis approaches typically use averaging or linear regression to remove this physiological baseline with varying degrees of success. Biophysical model-based analysis of the functional hemodynamic response has also been advanced previously with the Balloon and Windkessel models. In the present work, a biophysical model of systemic and cerebral circulation and gas exchange is applied to resting state NIRS neuroimaging data from 10 human subjects. The model further includes dynamic cerebral autoregulation, which modulates the cerebral arteriole compliance to control cerebral blood flow. This biophysical model allows for prediction, from noninvasive blood pressure measurements, of the background hemodynamic fluctuations in the systemic and cerebral circulations. Significantly higher correlations with the NIRS data were found using the biophysical model predictions compared to blood pressure regression and compared to transfer function analysis (multifactor ANOVA, p<0.0001). This finding supports the further development and use of biophysical models for removing baseline activity in functional neuroimaging analysis. Future extensions of this work could model changes in cerebrovascular physiology that occur during development, aging, and disease.
Evaluating cerebral oxygenation is of critical importance for the understanding of brain function and several neuropathologies. Although several techniques exist for measuring cerebral oxygenation in vivo, the most widely accepted techniques offer limited spatial resolution. We have developed a confocal imaging system for minimally invasive measurement of oxygen tension (pO(2)) in cerebral microvessels with high spatial and temporal resolution. The system relies on the phosphorescence quenching method using exogenous porphyrin-based dendritic oxygen probes. Here we present high-resolution phosphorescence images of cortical microvasculature and temporal pO(2) profiles from multiple locations in response to varied fraction of inspired oxygen and functional activation.
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