Key Aspects of Neurovascular Control Mediated by Specific Populations of Inhibitory Cortical Interneurons.

Inhibitory interneurons can evoke vasodilation and vasoconstriction, making them potential cellular drivers of neurovascular coupling. However, the specific regulatory roles played by particular interneuron subpopulations remain unclear. Our purpose was therefore to adopt a cell-specific optogenetic approach to investigate how somatostatin (SST) and neuronal nitric oxide synthase (nNOS)-expressing interneurons might influence the neurovascular relationship. In mice, specific activation of SST- or nNOS-interneurons was sufficient to evoke hemodynamic changes. In the case of nNOS-interneurons, robust hemodynamic changes occurred with minimal changes in neural activity, suggesting that the ability of blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) to reliably reflect changes in neuronal activity may be dependent on type of neuron recruited. Conversely, activation of SST-interneurons produced robust changes in evoked neural activity with shallow cortical excitation and pronounced deep layer cortical inhibition. Prolonged activation of SST-interneurons often resulted in an increase in blood volume in the centrally activated area with an accompanying decrease in blood volume in the surrounding brain regions, analogous to the negative BOLD signal. These results demonstrate the role of specific populations of cortical interneurons in the active control of neurovascular function.

Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease.

Our understanding of the underlying biology of Alzheimer's disease (AD) has been steadily progressing; however, this is yet to translate into a successful treatment in humans. The use of transgenic mouse models has helped to develop our understanding of AD, not only in terms of disease pathology, but also with the associated cognitive impairments typical of AD. Plaques and neurofibrillary tangles are often among the last pathological changes in AD mouse models, after neuronal loss and gliosis. There is a general consensus that successful treatments need to be applied before the onset of these pathologies and associated cognitive symptoms. This review discusses the different types of AD mouse models in terms of the temporal progression of the disease, how well they replicate the pathological changes seen in human AD and their cognitive defects. We provide a critical assessment of the behavioural tests used with AD mice to assess cognitive changes and decline, and discuss how successfully they correlate with cognitive impairments in humans with AD. This information is an important tool for AD researchers when deciding on appropriate mouse models, and when selecting measures to assess behavioural and cognitive change.

Kinetic modeling of hyperpolarized (13)C pyruvate metabolism in tumors using a measured arterial input function.

Mathematical models are required to estimate kinetic parameters of [1-(13)C] pyruvate-lactate interconversion from magnetic resonance spectroscopy data. One- or two-way exchange models utilizing a hypothetical approximation to the true arterial input function (AIF), (e.g. an ideal 'box-car' function) have been used previously. We present a method for direct measurement of the AIF in the rat. The hyperpolarized [1-(13)C] pyruvate signal was measured in arterial blood as it was continuously withdrawn through a small chamber. The measured signal was corrected for T1 relaxation of pyruvate, RF pulses and dispersion of blood in the chamber to allow for the estimation of the direct AIF. Using direct AIF, rather than the commonly used box-car AIF, provided realistic estimates of the rate constant of conversion of pyruvate to lactate, kpl, the rate constant of conversion of lactate to pyruvate klp, the clearance rate constant of pyruvate from blood to tissue, Kip, and the relaxation rate of lactate T1la. Since no lactate signal was present in blood, it was possible to use a simple precursor-product relationship, with the tumor tissue pyruvate time-course as the input for the lactate time-course. This provided a robust estimate of kpl, similar to that obtained using a directly measured AIF.

A novel method for classifying cortical state to identify the accompanying changes in cerebral hemodynamics.

BACKGROUND: Many brain imaging techniques interpret the haemodynamic response as an indirect indicator of underlying neural activity. However, a challenge when interpreting this blood based signal is how changes in brain state may affect both baseline and stimulus evoked haemodynamics. NEW METHOD: We developed an Automatic Brain State Classifier (ABSC), validated on data from anaesthetised rodents. It uses vectorised information obtained from the windowed spectral frequency power of the Local Field Potential. Current state is then classified by comparing this vectorised information against that calculated from state specific training datasets. RESULTS: The ABSC identified two user defined brain states (synchronised and desynchronised), with high accuracy (∼90%). Baseline haemodynamics were found to be significantly different in the two identified states. During state defined periods of elevated baseline haemodynamics we found significant decreases in evoked haemodynamic responses to somatosensory stimuli. COMPARISON TO EXISTING METHODS: State classification - The ABSC (∼90%) demonstrated greater accuracy than clustering (∼66%) or 'power threshold' (∼64%) methods of comparison. Haemodynamic averaging - Our novel approach of selectively averaging stimulus evoked haemodynamic trials by brain state yields higher quality data than creating a single average from all trials. CONCLUSIONS: The ABSC can account for some of the commonly observed trial-to-trial variability in haemodynamic responses which arises from changes in cortical state. This variability might otherwise be incorrectly attributed to alternative interpretations. A greater understanding of the effects of cortical state on haemodynamic changes could be used to inform techniques such as general linear modelling (GLM), commonly used in fMRI.

Cocaine administration produces a protracted decoupling of neural and haemodynamic responses to intense sensory stimuli.

Evidence suggests that for relatively weak sensory stimuli, cocaine elevates background haemodynamic parameters but still allows enhanced neural responses to be reflected in enhanced haemodynamic responses. The current study investigated the possibility that for more intense stimuli, the raised background may produce a protracted attenuation of the haemodynamic response. Three experiments were performed to measure effects of i.v. cocaine administration (0.5 mg/kg) or saline on responses in rat barrel cortex to electrical stimulation of the whisker pad. The first experiment used optical imaging spectroscopy (OIS) and laser Doppler flowmetry (LDF) to measure haemodynamic changes. Cocaine caused an increase in baseline blood flow (peak approximately 90%), which lasted for the duration of the test period (25 min). Haemodynamic responses to whisker stimulation were substantially reduced throughout. The second experiment used a 16-channel multi-electrode to measure evoked potentials at 100 mum intervals through the barrel cortex. Summed neural responses (collapsed across the spatial dimension) after cocaine administration were similar to those after saline. The third experiment extended experiment 1 by examining the effects of cocaine on whisker sensory responses using functional magnetic resonance imaging (and concurrent OIS or LDF). Cocaine caused a similar increase in baseline and reduction in the evoked response to that seen in experiment 1. Together, the results of these three experiments show that cocaine produces a protracted decoupling of neural activity and haemodynamic responses to intense sensory stimulation, which suggests that imaging techniques based on changes in haemodynamic parameters may be unsuitable for studying the effects of cocaine on sensory processing in humans.

Pseudo-random procedures for rapid presentation rates using optical imaging and spectroscopy.

Optical imaging of rat barrel cortex has provided detailed spatio-temporal maps of functional cortical architecture. We describe an event-related procedure (ERP) for optical imaging based on selective signal averaging as reported by Burock et al., using an anti-correlative pseudo-random event sequence. The sequence used 1 s vibrissal stimulation at 5 Hz, with an interevent interval of 2 s. This rapid presentation rate allows for greater statistical power per unit time, and allows for direct comparison of event-related studies with other imaging modalities. The spatio-temporal characteristics of single wavelength and spectrographic results were found to be comparable with those obtained by standard techniques, although a general lessening of haemodynamic response function (HRF) was noted. We also describe a method of locating barrel activity by spectral analysis of summed event data. Using this technique, the power spectrum of remitted light from the barrel region was found to peak within +/- 0.12 Hz of the inter-event interval frequency.

Integration of neural responses originating from different regions of the cortical somatosensory map.

The neural pathways responsible for detecting peripheral tactile stimuli are well known; however, the interactions between different somatosensory regions have been less well investigated. This study demonstrates how the contralateral sensory response of rat barrel cortex to whisker stimulation is affected by stimulation of contralateral forepaw and ipsilateral whisker and forepaw. The barrel cortex in the right hemisphere was located using optical imaging. A 16-channel multielectrode was used to measure field potentials evoked by contralateral electrical stimulation of the whisker pad. A standard response in the right barrel cortex to single pulse electrical stimulation of the contralateral whisker pad was modulated by applying conditioning stimulation to one of three other regions of the body (the ipsilateral whisker pad, the ipsilateral or contralateral forepaws). In conditions where the standard contralateral whisker stimulus preceded the conditioning pulse, the size of response was identical to when it was stimulated alone. However, when the ipsilateral whisker and contralateral forepaw conditioning stimuli preceded the contralateral whisker pad stimulation, up to a 35% reduction in the contralateral whisker response was observed. These results confirm and extend previous studies [Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 11026-11031; J. Neurosci. 21 (2001) 5251-5261], which show bilateral integration of neural activity within the rat somatosensory system. Furthermore, the longer latency of the inhibition following stimulation of the contralateral forepaw suggests the possible involvement of extracortical circuitry.

Fine detail of neurovascular coupling revealed by spatiotemporal analysis of the hemodynamic response to single whisker stimulation in rat barrel cortex.

The spatial resolution of hemodynamic-based neuroimaging techniques, including functional magnetic resonance imaging, is limited by the degree to which neurons regulate their blood supply on a fine scale. Here we investigated the spatial detail of neurovascular events with a combination of high spatiotemporal resolution two-dimensional spectroscopic optical imaging, multichannel electrode recordings and cytochrome oxidase histology in the rodent whisker barrel field. After mechanical stimulation of a single whisker, we found two spatially distinct cortical hemodynamic responses: a transient response in the "upstream" branches of surface arteries and a later highly localized increase in blood volume centered on the activated cortical column. Although the spatial representation of this localized response exceeded that of a single "barrel," the spread of hemodynamic activity accurately reflected the neural response in neighboring columns rather than being due to a passive "overspill." These data confirm hemodynamics are capable of providing accurate "single-condition" maps of neural activity.

Delayed onset muscle soreness does not alter O2 uptake kinetics during heavy-intensity cycling in humans.

The purpose of this study was to determine if exercise-induced delayed onset muscle soreness (DOMS) would alter O2 uptake kinetics during heavy cycling in 9 untrained females. O2 uptake kinetics were characterised during 8-min of constant-load cycling performed with and without DOMS. DOMS was caused by completing 30 min of bench-stepping at a rate of 15 steps.min(-1). Two days after bench stepping, all subjects reported significant leg muscle soreness. Both phase II kinetics (without DOMS tau1: 26.6 +/- 2.4 s; with DOMS tau1: 27.2 +/- 3.7 s) and the slow component amplitude (without DOMS: 277 +/- 15 mL.min(-1); with DOMS: 291 +/- 21 mL.min(-1)) were unaffected by DOMS. The change in blood lactate concentration from rest to end-exercise was significantly greater during exercise performed with DOMS. Eccentric exercise causing a moderate degree of DOMS does not appear to impact upon the mechanisms mediating phase II or the slow component of O2 uptake kinetics.

Neurovascular coupling investigated with two-dimensional optical imaging spectroscopy in rat whisker barrel cortex.

Optical imaging slit spectroscopy is a powerful method for estimating quantitative changes in cerebral haemodynamics, such as deoxyhaemoglobin, oxyhaemoglobin and blood volume (Hbr, HbO2 and Hbt, respectively). Its disadvantage is that there is a large loss of spatial data as one image dimension is used to encode spectral wavelength information. Single wavelength optical imaging, on the other hand, produces high-resolution spatiotemporal maps of brain activity, but yields only indirect measures of Hbr, HbO2 and Hbt. In this study we perform two-dimensional optical imaging spectroscopy (2D-OIS) in rat barrel cortex during contralateral whisker stimulation to obtain two-dimensional maps over time of Hbr, HbO2 and Hbt. The 2D-OIS was performed by illuminating the cortex with four wavelengths of light (575, 559, 495 and 587 nm), which were presented sequentially at a high frame rate (32 Hz). The contralateral whisker pad was stimulated using two different durations: 1 and 16 s (5 Hz, 1.2 mA). Control experiments used a hypercapnic (5% CO2) challenge to manipulate baseline blood flow and volume in the absence of corresponding neural activation. The 2D-OIS method allowed separation of artery, vein and parenchyma regions. The magnitude of the haemodynamic response elicited varied considerably between different vascular compartments; the largest responses in Hbt were in the arteries and the smallest in the veins. Phase lags in the HbO2 response between arteries and veins suggest that a process of upstream signalling maybe responsible for dilating the arteries. There was also a consistent increase in Hbr from arterial regions after whisker stimulation.

VE and VCO2 remain tightly coupled during incremental cycling performed after a bout of high-intensity exercise.

The purpose of the present study was to determine whether the linear relationship between CO2 output (VCO2) and pulmonary ventilation (VE) is altered during incremental cycling performed after exercise-induced metabolic acidosis. Ten untrained, female subjects performed two incremental cycling tests (15 W x min(-1) up to 165 W) on separate days. One incremental exercise test was conducted without prior exercise, whereas the other test was preceded by a 1-min bout of maximal cycling. The ventilatory equivalent for O2 (VE/VO2) was only elevated above control values at 15-60 W during incremental cycling performed after high-intensity exercise. In contrast, the ventilatory equivalent for CO2 (VE/VCO2) was significantly increased above control levels at nearly every work stage of incremental work (all except 165 W). Hyperventilation relative to VCO2 was confirmed by the significantly lower end-tidal CO2 tension (P(ET)CO2) obtained throughout the incremental cycling that was performed after high-intensity exercise (except at 165 W). VE and VCO2 were significantly correlated under both treatment conditions (r > 0.99; P < 0.001). Moreover, both the slope and y-intercept of the linear regression were found to be significantly elevated during the incremental cycling performed after high-intensity cycling compared to control conditions (P < 0.01). The increase in the slope of the VE-VCO2 relationship during incremental exercise performed under these conditions does not represent an uncoupling of VE from VCO2, but could be accounted for by the significantly lower P(ET)CO2 observed during exercise.

Effects of a chlorhexidine gluconate oral rinse on the incidence of alveolar osteitis in mandibular third molar surgery.

Alveolar osteitis (dry socket) continues to be a frequent sequela of third molar surgery. Chlorhexidine 0.12% used as an oral rinse has been reported to reduce the incidence of dry socket. This study compares the effectiveness of 0.12% chlorhexidine used as a preoperative rinse and immediate postextraction irrigant with 1) similarly used 0.05% cetylpyridium, preoperative chlorhexidine rinse and postextraction saline irrigation, and 2) only postextraction irrigation with normal saline in the reduction of alveolar osteitis in mandibular third molar extractions. The results indicate that chlorhexidine and cetylpyridium were no more effective in the reduction of alveolar osteitis than postextraction irrigation with normal saline.

Brachial plexus injury occurring during oral and maxillofacial surgery: a case report.

A case of brachial plexus injury occurring during bilateral temporomandibular joint reconstruction is reported. Patient positioning during surgery is the key to prevention of such injuries.

Signal source separation in the analysis of neural activity in brain.

This research examines the spatial and temporal characteristics of the responses to stimulation of the barrel cortex in anesthetized rats using optical imaging with particular emphasis on methods of analysis which reduce the effects of low-frequency oscillations on localization of the activated cortical region. Image sequences were captured using a light source with a narrow bandwidth of wavelength (590 +/- 2 nm). On each trial image data were collected at 15 Hz and stored over a 12-s period starting 8 s before stimulation onset. Stimulation was for 1 s using an oscillating whisker vibrator (approximately 1-mm deflection at 5 Hz). For each subject a total of 30 experimental trials were collected and averaged. There was an interstimulus interval of 26 s. The trial-averaged data were analyzed using two related signal source separation algorithms. Both algorithms use a weak model of the expected temporal response as a filter to exclude contributions from low-frequency baseline oscillations which we call the V-signal. We found that both algorithms successfully separated most of the effects of the V-signal from the response to the stimulation. The performance of the algorithms compared favorably with the performance of related algorithms without weak constraints and the "ratio of means" strategy used by C. H. Chen-Bee et al. (1996b, J. Neurosci. Methods 68:28-37; C. H. Chen-Bee et al., 2000, J. Neurosci. Methods 97:157-173).

Concurrent optical imaging spectroscopy and laser-Doppler flowmetry: the relationship between blood flow, oxygenation, and volume in rodent barrel cortex.

Functional magnetic resonance imaging (fMRI) is based on the coupling between neural activity and changes in the concentration of the endogenous paramagnetic contrast agent deoxygenated hemoglobin. Changes in the blood oxygen level-dependent (BOLD) signal result from a complex interplay of blood volume, flow, and oxygen consumption. Optical imaging spectroscopy (OIS) has been used to measure changes in blood volume and saturation in response to increased neural activity, while laser Doppler Flowmetry (LDF) can be used to measure flow changes and is now commonplace in neurovascular research. Here, we use concurrent OIS and LDF to examine the hemodynamic response in rodent barrel cortex using electrical stimulation of the whisker pad at varying intensities. Spectroscopic analysis showed that stimulation produced a biphasic early increase in deoxygenated hemoglobin (Hbr), followed by a decrease below baseline, reaching minima at approximately 3.7 s. There was no evidence for a corresponding early decrease in oxygenated hemoglobin (HbO(2)), which simply increased after stimulation, reaching maximum at approximately 3.2 s. The time courses of changes in blood volume (CBV) and blood flow (CBF) were similar. Both increased within a second of stimulation onset and peaked at approximately 2.7 s, after which CBV returned to baseline at a slower rate than CBF. The changes in Hbr, Hbt, and CBF were used to estimate changes in oxygen consumption (CMRO(2)), which increased within a second of stimulation and peaked approximately 2.2 s after stimulus onset. Analysis of the relative magnitudes of CBV and CBF indicates that the fractional changes of CBV could be simply scaled to match those of CBF. We found the relationship to be well approximated by CBV = CBF(0.29). A similar relationship was found using the response to elevated fraction of inspired carbon dioxide (FICO(2)).

Spectroscopic analysis of neural activity in brain: increased oxygen consumption following activation of barrel cortex.

This research investigates the hemodynamic response to stimulation of the barrel cortex in anaesthetized rats using optical imaging and spectroscopy (Bonhoeffer and Grinvald, 1996; Malonek and Grinvald, 1996; Mayhew et al., 1999). A slit spectrograph was used to collect spectral image data sequences. These were analyzed using an algorithm that corrects for the wavelength dependency in the optical path lengths produced by the light scattering properties of tissue. The analysis produced the changes in the oxy- and deoxygenation of hemoglobin following stimulation. Two methods of stimulation were used. One method mechanically vibrated a single whisker, the other electrically stimulated the whisker pad. The electrical stimulation intensity varied from 0.4 to 1.6 mA. The hemodynamic responses to stimulation increased as a function of intensity. At 0.4 mA they were commensurate with those from the mechanical stimulation; however, the responses at the higher levels were greater by a factor of approximately 10. For both methods of data collection, the results of the spectroscopic analysis showed an early increase in deoxygenated hemoglobin (Hbr) with no evidence for a corresponding decrease in oxygenated hemoglobin (HbO(2)). Evidence for increased oxygen consumption (CMRO(2)) was obtained by converting the fractional changes in blood volume (Hbt) into estimates of changes in blood flow (Grubb et al., 1974) and using the resulting time course to scale the fractional changes in Hbr. The results show an early increase CMRO(2) peaking approximately 2 s after stimulation onset. Using these methods, we find evidence for increased oxygen consumption following increased neural activity even at low levels of stimulation intensity.

Creatine supplementation and the total work performed during 15-s and 1-min bouts of maximal cycling.

Nine untrained male subjects participated in a placebo (Pl)/creatine (Cr), single-blind study conducted over a 5-wk period. Placebo and Cr treatments were presented in a sequential manner because muscle Cr washout time after supplementation is unknown. The mean ( +/- SE) age, height, and initial body mass for the subjects was 25.7+/- 1.2 yr, 177 +/- 2 cm, and 78.5 +/- 3.8 kg, respectively. Each subject performed five 15-s bouts of maximal cycling (1-min rest periods) after 7 d of Pl (6 g glucose X 5 doses daily) and again after ingesting Cr for 7 d (5 g creatine plus 1 g glucose X 5 doses) with a 2-wk intervention period. Only 6 of 9 subjects were able to complete five 1-min bouts of maximal cycling (5-min rest periods) after an additional 2 d of Pl and Cr treatment. Cr ingestion resulted in a significant increase in the work performed during each 15-s bout of maximal cycling compared to Pl trials. Moreover, the total work completed during five 15-s bouts of cycling increased significantly from 47.5 +/- 2.3 kJ with Pl treatment to 50.6 +/- 2.3 kJ after Cr supplementation (P < 0.05). Peak blood lactate concentrations determined 4 min after the fifth 15-s work bout were 14.4 +/- 0.5 mmol.L-1 and 14.3 +/- mmol.L-1 for Pl and Cr trials, respectively (P < 0.05). Total work completed during five 1-min bouts of maximal cycling was not significantly increased after Cr supplementation (P > 0.05). Additionally, Cr supplementation did not slow the rate of decline in the work accomplished during repeated bouts of maximal cycling. These findings suggest that Cr ingestion may augment the rate of ATP resynthesis from phosphocreatine during exercise in untrained subjects.

Spectroscopic analysis of changes in remitted illumination: the response to increased neural activity in brain.

Imaging of neural activation has been used to produce maps of functional architecture and metabolic activity. There is some uncertainty associated with the sources underlying the intrinsic signals. It has been reported that following increased neural activity there was little increased oxygen consumption ( approximately 5%), although glucose consumption increased by approximately 50%. The research we describe uses a modification of the Beer-Lambert Law called path-length scaling analysis (PLSA) to analyze the spectra of the hemodynamic and metabolic responses to vibrissal stimulation in rat somatosensory cortex. The results of the PLSA algorithm were compared with those obtained using a linear spectrographic analysis method (we refer to this as LMCA). There are differences in the results of the analysis depending on which of the two algorithms (PLSA or LMCA) is used. Using the LMCA algorithm, we obtain results showing an increase in the volume of Hbr at approximately 2 s, following onset of stimulation but no complementary decrease in oxygenated haemoglobin (HbO(2)). These results are similar to a previous report. In contrast, after using the PLSA algorithm, the time series of the chromophore changes shows no evidence for an increase in the volume of deoxygenated haemoglobin (Hbr). However, after further analysis of the time series from the PLSA using general linear models (GLM) to remove contributions from low frequency baseline oscillations, both the HbO(2) and Hbr times series of the response to stimulation were found to be biphasic with an early decrease in saturation peaking approximately 1 s after onset of stimulation followed by a larger increase in saturation peaking at approximately 3 s. Finally, following the PLSA-then-GLM analysis procedure, we do not find convincing evidence for an increase in cytochrome oxidation following stimulation, though we demonstrate the PLSA algorithm to be capable of disassociating changes in cytochrome oxidation state from changes in hemoglobin oxygenation.

Increased oxygen consumption following activation of brain: theoretical footnotes using spectroscopic data from barrel cortex.

Optical imaging spectroscopy (OIS) and laser Doppler flowmetry (LDF) data sequences from anesthetized rats were used to determine the relationship between changes in oxy-and deoxygenated hemoglobin concentration and changes in blood volume and flow in the presence and absence of stimulation. The data from Jones et al. (accompanying paper) were used to explore the differences between two theoretical models of flow activation coupling. The essential difference between the two models is the extension of the model of Buxton and Frank by Hyder et al. (1998, J. Appl. Physiol. 85: 554--564) to incorporate change in capillary diffusivity coupled to flow. In both models activation-increased flow changes increase oxygen transport from the capillary; however, in Hyder et al.'s model the diffusivity of the capillary itself is increased. Hyder et al. proposed a parameter (Omega), a scaling "constant" linking increased blood flow and oxygen "diffusivity" in the capillary bed. Thus, in Buxton and Frank's theory, Omega = 0; i.e., there are no changes in diffusivity. In Hyder et al.'s theory, 0 < Omega < 1, and changes in diffusivity are assumed to be linearly related to flow changes. We elaborate the theoretical position of both models to show that, in principle, the different predictions from the two theories can be evaluated using optical imaging spectroscopy data. We find that both theoretical positions have limitations when applied to data from brief stimulation and when applied to data from mild hypercapnia. In summary, the analysis showed that although Hyder et al.'s proposal that diffusivity increased during activation did occur; it was shown to arise from an implementation of Buxton and Frank's theory under episodes of brief stimulation. The results also showed that the scaling parameter Omega is not a constant as the Hyder et al. model entails but in fact varies over the time course of the flow changes. Data from experiments in which mild hypercapnia was administered also indicated changes in the diffusivity of the capillary bed, but in this case the changes were negative; i.e., oxygen transport from the capillary decreased relative to baseline under hypercapnia. Neither of the models could account for the differences between the hypercapnia and activation data when matched for equivalent flow changes. A modification to the models to allow non-null tissue oxygen concentrations that can be moderated by changes due to increased metabolic demand following increased neural activity is proposed. This modification would allow modulation of oxygen transport from the capillary bed (e.g., changes in diffusivity) by tissue oxygen tension and would allow a degree of decoupling of flow and oxygen delivery, which can encompass both the data from stimulation and from hypercapnia.