Keller, Corey J. | Cash, Sydney S. | Narayanan, Suresh | Wang, Chunmao | Kuzniecky, Ruben | Carlson, Chad | Devinsky, Orrin | Thesen, Thomas | Doyle, Werner | Sassaroli, Angelo | Boas, David A. | Ulbert, Istvan | Halgren, Eric
Measurement of the blood-oxygen-level dependent (BOLD) response with fMRI has revolutionized cognitive neuroscience and is increasingly important in clinical care. The BOLD response reflects changes in deoxy-hemoglobin concentration, blood volume, and blood flow. These hemodynamic changes ultimately result from neuronal firing and synaptic activity, but the linkage between these domains is complex, poorly understood, and may differ across species, cortical areas, diseases, and cognitive states. We describe here a technique that can measure neural and hemodynamic changes simultaneously from cortical microdomains in waking humans. We utilize a “laminar optode,” a linear array of microelectrodes for electrophysiological measures paired with a micro-optical device for hemodynamic measurements. Optical measurements include laser Doppler to estimate cerebral blood flow as well as point spectroscopy to estimate oxy- and deoxy-hemoglobin concentrations. The microelectrode array records local field potential gradients (PG) and multi-unit activity (MUA) at 24 locations spanning the cortical depth, permitting estimation of population trans-membrane current flows (Current Source Density, CSD) and population cell firing in each cortical lamina. Comparison of the laminar CSD/MUA profile with the origins and terminations of cortical circuits allows activity in specific neuronal circuits to be inferred and then directly compared to hemodynamics. Access is obtained in epileptic patients during diagnostic evaluation for surgical therapy. Validation tests with relatively well-understood manipulations (EKG, breath-holding, cortical electrical stimulation) demonstrate the expected responses. This device can provide a new and robust means for obtaining detailed, quantitative data for defining neurovascular coupling in awake humans.
doi:10.1016/j.jneumeth.2009.01.036
PMCID: PMC2680793
PMID: 19428529
microelectrode; BOLD; oxygenation; hemodynamics; neuro-hemodynamic coupling; breath-hold; electrocardiogram; cortical electrical stimulation
Diffuse optics has proven useful for quantitative assessment of tissue oxy- and deoxyhaemoglobin concentrations and, more recently, for measurement of microvascular blood flow. In this paper, we focus on the flow monitoring technique: diffuse correlation spectroscopy (DCS). Representative clinical and pre-clinical studies from our laboratory illustrate the potential of DCS. Validation of DCS blood flow indices in human brain and muscle is presented. Comparison of DCS with arterial spin-labelled MRI, xenon-CT and Doppler ultrasound shows good agreement (0.50
doi:10.1098/rsta.2011.0232
PMCID: PMC3263785
PMID: 22006897
diffuse correlation spectroscopy; blood flow; cerebral blood flow; oxygen metabolism; brain; cancer
Diffuse optical imaging (DOI) is a non invasive technique allowing the recovery of hemodynamic changes in the brain. Due to the diffusive nature of photon propagation in turbid media and the fact that cerebral tissues are located around 1.5 cm under the adult human scalp, DOI measurements are subject to partial volume errors. DOI measurements are also sensitive to large pial vessels because oxygenated and deoxygenated hemoglobin are the dominant chromophores in the near infrared window. In this study, the effect of the extra-cerebral vasculature in proximity of the sagittal sinus was investigated for its impact on DOI measurements simulated over the human adult visual cortex. Numerical Monte Carlo simulations were performed on two specific models of the human head derived from magnetic resonance imaging (MRI) scans. The first model included the extra-cerebral vasculature in which constant hemoglobin concentrations were assumed while the second did not. The screening effect of the vasculature was quantified by comparing recovered hemoglobin changes from each model for different optical arrays and regions of activation. A correction factor accounting for the difference between the recovered and the simulated hemoglobin changes was computed in each case. The results show that changes in hemoglobin concentration are better estimated when the extra-cerebral vasculature is modeled and the correction factors obtained in this case were at least 1.4-fold lower. The effect of the vasculature was also examined in a high-density diffuse optical tomography configuration. In this case, the difference between changes in hemoglobin concentration recovered with each model was reduced down to 10%.
doi:10.1364/BOE.2.000680
PMCID: PMC3047372
PMID: 21412472
(170.3660) Light propagation in tissues; (110.3080) Infrared imaging; (170.5280) Photon migration
Epileptic events elicit a large focal increase in cerebral blood flow (CBF) to perfuse metabolically active neurons in the focus. Conflicting data exists, however, on whether hemoglobin saturation increases or decreases in the focus and surrounding cortex, and whether CBF increases globally or is decreased in adjacent areas. How these hemodynamic events correlate with actual changes in tissue oxygenation is also not known. Using laser Doppler flowmetry, oxygen microsensors and intrinsic optical imaging spectroscopy, we demonstrate that the dip in hemoglobin in the focus correlates with a profound but temporary decrease in tissue oxygenation in spite of a large increase in cerebral blood flow (CBF). Furthermore, CBF simultaneously decreases in the cortex immediately adjacent to the focus. These events are then replaced with a longer duration, less focal increase in CBF, CBV and hyperoxygenation, the duration of which correlates with the duration of the seizure. These findings raise the question of whether transient focal hypoxia and vascular steal might contribute to progressive deleterious effects of chronic epilepsy on the adult and developing brain. Possible mechanisms based on recent astrocyte-based models of neurovascular coupling are discussed. Implications for functional magnetic resonance imaging of epileptic events are discussed.
doi:10.1523/JNEUROSCI.4667-08.2009
PMCID: PMC2745405
PMID: 19261877
Cerebral blood flow; cerebral cortex; epilepsy; optical imaging; seizure; tissue oxygen
Rotational inertial forces are thought to be the underlying mechanism for most severe brain injuries. However, little is known about the effect of head rotation direction on injury outcomes, particularly in the pediatric population. Neonatal piglets were subjected to a single non-impact head rotation in the horizontal, coronal, or sagittal direction, and physiological and histopathological responses were observed. Sagittal rotation produced the longest duration of unconsciousness, highest incidence of apnea, and largest intracranial pressure increase, while coronal rotation produced little change, and horizontal rotation produced intermediate and variable derangements. Significant cerebral blood flow reductions were observed following sagittal but not coronal or horizontal injury compared to sham. Subarachnoid hemorrhage, ischemia, and brainstem pathology were observed in the sagittal and horizontal groups but not in a single coronal animal. Significant axonal injury occurred following both horizontal and sagittal rotations. For both groups, the distribution of injury was greater in the frontal and parietotemporal lobes than in the occipital lobes, frequently occurred in the absence of ischemia, and did not correlate with regional cerebral blood flow reductions. We postulate that these direction-dependent differences in injury outcomes are due to differences in tissue mechanical loading produced during head rotation.
doi:10.1016/j.expneurol.2010.09.015
PMCID: PMC3021173
PMID: 20875409
animal models; brain ischemia; brain trauma; cerebral blood flow; neuropathology; subarachnoid hemorrhage
Little is known about cerebral blood flow, cerebral blood volume (CBV), oxygenation, and oxygen consumption in the premature newborn brain. We combined quantitative frequency-domain near-infrared spectroscopy measures of cerebral hemoglobin oxygenation (SO2) and CBV with diffusion correlation spectroscopy measures of cerebral blood flow index (BFix) to determine the relationship between these measures, gestational age at birth (GA), and chronological age. We followed 56 neonates of various GA once a week during their hospital stay. We provide absolute values of SO2 and CBV, relative values of BFix, and relative cerebral metabolic rate of oxygen (rCMRO2) as a function of postmenstrual age (PMA) and chronological age for four GA groups. SO2 correlates with chronological age (r=−0.54, P value ⩽0.001) but not with PMA (r=−0.07), whereas BFix and rCMRO2 correlate better with PMA (r=0.37 and 0.43, respectively, P value ⩽0.001). Relative CMRO2 during the first month of life is lower when GA is lower. Blood flow index and rCMRO2 are more accurate biomarkers of the brain development than SO2 in the premature newborns.
doi:10.1038/jcbfm.2011.145
PMCID: PMC3293111
PMID: 22027937
brain hemodynamic development; cerebral oxygen consumption; diffuse correlation spectroscopy; frequency-domain near-infrared spectroscopy; premature neonates
Durduran, Turgut | Zhou, Chao | Edlow, Brian L | Yu, Guoqiang | Choe, Regine | Kim, Meeri N | Cucchiara, Brett L | Putt, Mary E | Shah, Qaisar | Kasner, Scott E | Greenberg, Joel H | Yodh, Arjun G | Detre, John A
“Diffuse correlation spectroscopy” (DCS) is a technology for non-invasive transcranial measurement of cerebral blood flow (CBF) that can be hybridized with “near-infrared spectroscopy” (NIRS). Taken together these methods hold potential for monitoring hemodynamics in stroke patients. We explore the utility of DCS and NIRS to measure effects of head-of-bed (HOB) positioning at 30°, 15°, 0°, −5° and 0° angles in patients with acute ischemic stroke affecting frontal cortex and in controls. HOB positioning significantly altered CBF, oxy-hemoglobin (HbO2) and total-hemoglobin (THC) concentrations. Moreover, the presence of an ipsilateral infarct was a significant effect for all parameters. Results are consistent with the notion of impaired CBF autoregulation in the infarcted hemisphere.
PMCID: PMC2724658
PMID: 19259230
In this study, we tested the hypothesis that decreased cerebral perfusion pressure (CPP) induces cerebral ischemia and worsen brain damage in neonatal bacterial meningitis. Meningitis was induced by intracisternal injection of 10(9) colony forming units of Escherichia coli in 21 newborn piglets. Although CPP decreased significantly at 8 hr after bacterial inoculation, deduced hemoglobin (HbD), measured as an index of changes in cerebral blood flow by near infrared spectroscopy, did not decrease significantly. In correlation analyses, CPP showed significant positive correlation with brain ATP and inverse correlation with brain lactate levels. CPP also correlated positively with HbD and oxidized cytochrome aa3 (Cyt aa3) by near infrared spectroscopy. However, CPP did not show significant correlation with cerebral cortical cell membrane Na+,K+-ATPase activity, nor with levels of lipid peroxidation products. In summary, decreased CPP observed in this study failed to induce cerebral ischemia and further brain injury, indicating that cerebrovascular autoregulation is intact during the early phase of experimental neonatal bacterial meningitis.
PMCID: PMC3054608
PMID: 10803699
Modern non-invasive brain imaging techniques utilize changes in cerebral blood flow, volume and oxygenation that accompany brain activation. However, stimulus-evoked hemodynamic responses display considerable inter-trial variability even when identical stimuli are presented and the sources of this variability are poorly understood. One of the sources of this response variation could be ongoing spontaneous hemodynamic fluctuations. To investigate this issue, 2-dimensional optical imaging spectroscopy was used to measure cortical hemodynamics in response to sensory stimuli in anesthetized rodents. Pre-stimulus cortical hemodynamics displayed spontaneous periodic fluctuations and as such, data from individual stimulus presentation trials were assigned to one of four groups depending on the phase angle of pre-stimulus hemodynamic fluctuations and averaged. This analysis revealed that sensory evoked cortical hemodynamics displayed distinctive response characteristics and magnitudes depending on the phase angle of ongoing fluctuations at stimulus onset. To investigate the origin of this phenomenon, “null-trials” were collected without stimulus presentation. Subtraction of phase averaged “null trials” from their phase averaged stimulus-evoked counterparts resulted in four similar time series that resembled the mean stimulus-evoked response. These analyses suggest that linear superposition of evoked and ongoing cortical hemodynamic changes may be a property of the structure of inter-trial variability.
doi:10.3389/fnene.2010.00023
PMCID: PMC2938927
PMID: 20844602
optical-imaging; brain-imaging; barrel cortex; spontaneous fluctuations
Occlusions of bilateral common carotid arteries (bi-CCA) in mice are popular models for the investigation of transient forebrain ischemia. Currently available technologies for assessing cerebral blood flow (CBF) and oxygenation in ischemic mice have limitations. This study tests a novel near-infrared diffuse correlation spectroscopy (DCS) flow-oximeter for monitoring both CBF and cerebral oxygenation in mice undergoing repeated transient forebrain ischemia. Concurrent flow measurements in a mouse brain were first conducted for validation purposes; DCS measurement was found highly correlated with laser Doppler measurement (R2 = 0.94) and less susceptible to motion artifacts. With unique designs in experimental protocols and fiber-optic probes, we have demonstrated high sensitivities of DCS flow-oximeter in detecting the regional heterogeneity of CBF responses in different hemispheres and global changes of both CBF and cerebral oxygenation across two hemispheres in mice undergoing repeated 2-minute bi-CCA occlusions over 5 days. More than 75% CBF reductions were found during bi-CCA occlusions in mice, which may be considered as a threshold to determine a successful bi-CCA occlusion. With the progress of repeated 2-minute bi-CCA occlusions over days, a longitudinal decline in the magnitudes of CBF reduction was observed, indicating the brain adaptation to cerebral ischemia through the repeated preconditioning.
doi:10.1364/OE.19.020301
PMCID: PMC3495871
PMID: 21997041
(170.0170) Medical optics and biotechnology; (170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (170.6480) Spectroscopy, speckle
We present a broad-band, continuous-wave spectral approach to quantify the baseline optical
properties of tissue and changes in the concentration of a chromophore, which can assist to
quantify the regional blood flow from dynamic contrast-enhanced near-infrared spectroscopy
data. Experiments were conducted on phantoms and piglets. The baseline optical properties of
tissue were determined by a multi-parameter wavelength-dependent data fit of a photon diffusion
equation solution for a homogeneous medium. These baseline optical properties were used to find
the changes in Indocyanine green concentration time course in the tissue. The changes were
obtained by fitting the dynamic data at the peak wavelength of the chromophore absorption,
which were used later to estimate the cerebral blood flow using a bolus tracking method.
doi:10.1364/BOE.3.002761
PMCID: PMC3493236
PMID: 23162714
(300.6340) Spectroscopy, infrared; (290.5820) Scattering measurements; (290.1990) Diffusion
We describe a technique that uses spatially modulated near-infrared (NIR) illumination to detect and map changes in both optical properties (absorption and reduced scattering parameters) and tissue composition (oxy- and deoxyhemoglobin, total hemoglobin, and oxygen saturation) during acute ischemic injury in the rat barrel cortex. Cerebral ischemia is induced using an open vascular occlusion technique of the middle cerebral artery (MCA). Diffuse reflected NIR light (680 to 980 nm) from the left parietal somatosensory cortex is detected by a CCD camera before and after MCA occlusion. Monte Carlo simulations are used to analyze the spatial frequency dependence of the reflected light to predict spatiotemporal changes in the distribution of tissue absorption and scattering properties in the brain. Experimental results from seven rats show a 17±4.7% increase in tissue concentration of deoxyhemoglobin and a 45±3.1, 23±5.4, and 21±2.2% decrease in oxyhemoglobin, total hemoglobin concentration and cerebral tissue oxygen saturation levels, respectively, 45 min following induction of cerebral ischemia. An ischemic index (Iisch=ctHHb/ctO2Hb) reveals an average of more then twofold contrast after MCAo. The wavelength-dependence of the reduced scattering (i.e., scatter power) decreased by 35±10.3% after MCA occlusion. Compared to conventional CCD-based intrinsic signal optical imaging (ISOI), the use of structured illumination and model-based analysis allows for generation of separate maps of light absorption and scattering properties as well as tissue hemoglobin concentration. This potentially provides a powerful approach for quantitative monitoring and imaging of neurophysiology and metabolism with high spatiotemporal resolution.
doi:10.1117/1.3116709
PMCID: PMC2868516
PMID: 19405762
stroke; brain ischemia; structured light; tissue optical properties; diffuse optical imaging; cerebral hemodynamics
Diffuse optical tomography (DOT) is a non-invasive brain imaging technique that uses low-levels of near-infrared light to measure optical absorption changes due to regional blood flow and blood oxygen saturation in the brain. By arranging light sources and detectors in a grid over the surface of the scalp, DOT studies attempt to spatially localize changes in oxy- and deoxy-hemoglobin in the brain that result from evoked brain activity during functional experiments. However, the reconstruction of accurate spatial images of hemoglobin changes from DOT data is an ill-posed linearized inverse problem, which requires model regularization to yield appropriate solutions. In this work, we describe and demonstrate the application of a parametric restricted maximum likelihood method (ReML) to incorporate multiple statistical priors into the recovery of optical images. This work is based on similar methods that have been applied to the inverse problem for magnetoencephalography (MEG). Herein, we discuss the adaptation of this model to DOT and demonstrate that this approach provides a means to objectively incorporate reconstruction constraints and demonstrate this approach through a series of simulated numerical examples.
doi:10.1364/BOE.1.001084
PMCID: PMC3018091
PMID: 21258532
(170.3010) Image reconstruction techniques; (170.2655) Functional monitoring and imaging
Objective
This study characterized the association between endothelin-1, cerebral hemodynamics, and histopathology after fluid percussion brain injury in the newborn pig.
Methods
Lateral fluid percussion injury was induced in newborn pigs equipped with a closed cranial window. Cerebral blood flow was determined with radiolabeled microspheres and cerebrospinal fluid endothelin-1 was measured by radioimmunoassay.
Results
Cerebrospinal fluid endothelin-1 was increased from 26 ± 4 to 296 ± 37 pg/ml (~10−10M) at 8 hours following fluid percussion injury. Post-injury treatment (30 minutes) with the endothelin-1 antagonist BQ-123 (1 mg/kg, intravenous) blocked pial artery vasoconstriction to topical endothelin-1 (~10−10M) and blunted fluid percussion injury-induced reductions in cerebral blood flow at 8 hours post-insult (56 ± 6 and 26±4 ml/minute versus 57 ± 6 and 40 ± 4 ml/minute; 100 g for cerebral blood flow before injury and 8 hours post-fluid percussion injury in vehicle and BQ-123 post-treated animals, respectively). Fluid percussion injury resulted in neuronal cell loss and decreased microtubule associated protein 2 immunoreactivity in the parietal cortex, which were blunted by BQ-123.
Discussion
These data indicate that fluid percussion injury-induced changes in cerebral hemodynamics are associated with neuronal damage and that endothelin-1 contributes to fluid percussion injury-induced histopathologic changes.
doi:10.1179/016164111X12881719352138
PMCID: PMC3545647
PMID: 21801587
Cerebral hemodynamics; Pediatric traumatic brain injury; Endothelin; Histopathology
Objectives
Traumatic brain injury (TBI) causes an early reduction of cerebral blood flow (CBF). The purpose was to study cerebrovascular endothelial function by examining the reactivity of cerebral vessels to L-arginine.
Methods
Fifty-one patients with severe TBI were prospectively studied by measuring cerebral hemodynamics before and after the administration of L-arginine, 300 mg/kg at 12 hrs and at 48 hrs after injury. These hemodynamic measurements, using transcranial Doppler techniques, included internal carotid flow volume as an estimate of hemispheric cerebral blood flow, flow velocity in intracranial vessels, CO2 reactivity, and dynamic pressure autoregulation using thigh cuff deflation and carotid compression methods. Changes in the hemodynamics with L-arginine administration were analyzed using a general linear mixed model.
Results
L-arginine produced no change in mean arterial pressure, intracranial pressure, or brain oxygenation. Overall, L-arginine induced an 11.3% increase in internal carotid artery flow volume (p= .0190). This increase was larger at 48 hrs than at 12 hrs (p= .0045), and tended to be larger in the less injured hemisphere at both time periods. The response of flow velocity in the intracranial vessels was similar, but smaller differences with administration of L-arginine were observed. There was a significant improvement in CO2 reactivity with L-arginine, but no change in dynamic pressure autoregulation.
Discussion
The low response of the cerebral vessels to L-arginine at 12 hrs post-injury with improvement at 48hrs suggests that dysfunction of cerebrovascular endothelium plays a role in the reduced CBF observed after TBI.
doi:10.1179/016164110X12767786356598
PMCID: PMC2958228
PMID: 20712924
cerebral autoregulation; endothelial dysfunction; L-arginine; nitric oxide; traumatic brain injury
Traumatic brain injury is a global health concern and is the leading cause of traumatic morbidity and mortality in children. Despite a lower overall mortality than in adult traumatic brain injury, the cost to society from the sequelae of pediatric traumatic brain injury is very high. Predictors of poor outcome after traumatic brain injury include altered systemic and cerebral physiology, including altered cerebral hemodynamics. Cerebral autoregulation is often impaired following traumatic brain injury and may adversely impact poor outcome. Although altered cerebrovascular hemodynamics early after traumatic brain injury may contribute to disability in children, there is a paucity of information regarding changes in cerebral blood flow and cerebral autoregulation after pediatric traumatic brain injury. In this article, we discuss normal pediatric cerebral physiology and cerebrovascular pathophysiology following pediatric traumatic brain injury.
doi:10.1016/j.pediatrneurol.2007.09.012
PMCID: PMC2330089
PMID: 18358399
This study explored using a novel diffuse correlation spectroscopy (DCS) flow-oximeter to noninvasively monitor blood flow and oxygenation changes in head and neck tumors during radiation delivery. A fiber-optic probe connected to the DCS flow-oximeter was placed on the surface of the radiologically/clinically involved cervical lymph node. The DCS flow-oximeter in the treatment room was remotely operated by a computer in the control room. From the early measurements, abnormal signals were observed when the optical device was placed in close proximity to the radiation beams. Through phantom tests, the artifacts were shown to be caused by scattered x rays and consequentially avoided by moving the optical device away from the x-ray beams. Eleven patients with head and neck tumors were continually measured once a week over a treatment period of seven weeks, although there were some missing data due to the patient related events. Large inter-patient variations in tumor hemodynamic responses were observed during radiation delivery. A significant increase in tumor blood flow was observed at the first week of treatment, which may be a physiologic response to hypoxia created by radiation oxygen consumption. Only small and insignificant changes were found in tumor blood oxygenation, suggesting that oxygen utilizations in tumors during the short period of fractional radiation deliveries were either minimal or balanced by other effects such as blood flow regulation. Further investigations in a large patient population are needed to correlate the individual hemodynamic responses with the clinical outcomes for determining the prognostic value of optical measurements.
doi:10.1364/BOE.3.000259
PMCID: PMC3269843
PMID: 22312579
(170.0170) Medical optics and biotechnology; (170.3660) Light propagation in tissues; (170.3880) Medical and biological imaging; (170.6480) Spectroscopy, speckle
Adult near-infrared spectroscopy is a potential method for observing changes in cerebral oxygenation non-invasively. Access of light to the adult brain requires requires penetration through extracranial tissues; hence the detection of changes in cerebral chromophore concentration can only be achieved by using near-infrared spectroscopy in the reflectance-mode thereby adding variables which are difficult to control. These include the effects of variable anatomy, different intra-optode distances and the presence of an extra- to intracranial collateral blood supply. Although movements of oxygenated haemoglobin concentration following specific cerebral stimuli can be demonstrated, the challenge of separating changes which occur within the extracranial compartment from those occurring in the intracranial compartments remains. Our experience with near-infrared spectroscopy in the three adult clinical scenarios of carotid endarterectomy, head injury and carbon dioxide stress testing will be presented. The influence of extracranial contamination is demonstrated, as are the methods we have developed to help control for extracranial contamination. Provisional experience with spatially resolved spectroscopy technology will also be presented.
PMCID: PMC1691962
PMID: 9232858
In the last two decades, both diffuse optical tomography (DOT) and blood oxygen level dependent (BOLD)-based functional magnetic resonance imaging (fMRI) methods have been developed as noninvasive tools for imaging evoked cerebral hemodynamic changes in studies of brain activity. Although these two technologies measure functional contrast from similar physiological sources, i.e., changes in hemoglobin levels, these two modalities are based on distinct physical and biophysical principles leading to both limitations and strengths to each method. In this work, we describe a unified linear model to combine the complimentary spatial, temporal, and spectroscopic resolutions of concurrently measured optical tomography and fMRI signals. Using numerical simulations, we demonstrate that concurrent optical and BOLD measurements can be used to create cross-calibrated estimates of absolute micromolar deoxyhemoglobin changes. We apply this new analysis tool to experimental data acquired simultaneously with both DOT and BOLD imaging during a motor task, demonstrate the ability to more robustly estimate hemoglobin changes in comparison to DOT alone, and show how this approach can provide cross-calibrated estimates of hemoglobin changes. Using this multimodal method, we estimate the calibration of the 3 tesla BOLD signal to be −0.55% ± 0.40% signal change per micromolar change of deoxyhemoglobin.
doi:10.1117/1.2976432
PMCID: PMC2718838
PMID: 19021411
functional magnetic resonance imaging; near-infrared spectroscopy; diffuse optical tomography; multimodality imaging; Bayesian modeling
Lindauer, Ute | Leithner, Christoph | Kaasch, Heike | Rohrer, Benjamin | Foddis, Marco | Füchtemeier, Martina | Offenhauser, Nikolas | Steinbrink, Jens | Royl, Georg | Kohl-Bareis, Matthias | Dirnagl, Ulrich
Recently, a universal, simple, and fail-safe mechanism has been proposed by which cerebral blood flow (CBF) might be coupled to oxygen metabolism during neuronal activation without the need for any tissue-based mechanism. According to this concept, vasodilation occurs by local erythrocytic release of nitric oxide or ATP wherever and whenever hemoglobin is deoxygenated, directly matching oxygen demand and supply in every tissue. For neurovascular coupling in the brain, we present experimental evidence challenging this view by applying an experimental regime operating without deoxy-hemoglobin. Hyperbaric hyperoxygenation (HBO) allowed us to prevent hemoglobin deoxygenation, as the oxygen that was physically dissolved in the tissue was sufficient to support oxidative metabolism. Regional CBF and regional cerebral blood oxygenation were measured using a cranial window preparation in anesthetized rats. Hemodynamic and neuronal responses to electrical forepaw stimulation or cortical spreading depression (CSD) were analyzed under normobaric normoxia and during HBO up to 4 ATA (standard atmospheres absolute). Inconsistent with the proposed mechanism, during HBO, CBF responses to functional activation or CSD were unchanged. Our results show that activation-induced CBF regulation in the brain does not operate through the release of vasoactive mediators on hemoglobin deoxygenation or through a tissue-based oxygen-sensing mechanism.
doi:10.1038/jcbfm.2009.259
PMCID: PMC2949158
PMID: 20040927
ATP; cerebral blood flow; cortical spreading depression; feed-forward regulation; hyperbaric hyperoxygenation; somatosensory stimulation
