Post-stimulus fMRI and EEG responses: Evidence for a neuronal origin hypothesised to be inhibitory.

Post-stimulus undershoots, negative responses following cessation of stimulation, are widely observed in functional magnetic resonance (fMRI) blood oxygenation level dependent (BOLD) data. However, the debate surrounding whether the origin of this response phase is neuronal or vascular, and whether it provides functionally relevant information, that is additional to what is contained in the primary response, means that undershoots are widely overlooked. We simultaneously recorded electroencephalography (EEG), BOLD and cerebral blood-flow (CBF) [obtained from arterial spin labelled (ASL) fMRI] fMRI responses to hemifield checkerboard stimulation to test the potential neural origin of the fMRI post-stimulus undershoot. The post-stimulus BOLD and CBF signal amplitudes in both contralateral and ipsilateral visual cortex depended on the post-stimulus power of the occipital 8-13Hz (alpha) EEG neuronal activity, such that trials with highest EEG power showed largest fMRI undershoots in contralateral visual cortex. This correlation in post-stimulus EEG-fMRI responses was not predicted by the primary response amplitude. In the contralateral visual cortex we observed a decrease in both cerebral rate of oxygen metabolism (CMRO2) and CBF during the post-stimulus phase. In addition, the coupling ratio (n) between CMRO2 and CBF was significantly lower during the positive contralateral primary response phase compared with the post-stimulus phase and we propose that this reflects an altered balance of excitatory and inhibitory neuronal activity. Together our data provide strong evidence that the post-stimulus phase of the BOLD response has a neural origin which reflects, at least partially, an uncoupling of the neuronal responses driving the primary and post-stimulus responses, explaining the uncoupling of the signals measured in the two response phases. We suggest our results are consistent with inhibitory processes driving the post-stimulus EEG and fMRI responses. We therefore propose that new methods are required to model the post-stimulus and primary responses independently, enabling separate investigation of response phases in cognitive function and neurological disease.

Hypoxic pulmonary vasoconstriction does not contribute to pulmonary blood flow heterogeneity in normoxia in normal supine humans.

We hypothesized that some of the heterogeneity of pulmonary blood flow present in the normal human lung in normoxia is due to hypoxic pulmonary vasoconstriction (HPV). If so, mild hyperoxia would decrease the heterogeneity of pulmonary perfusion, whereas it would be increased by mild hypoxia. To test this, six healthy nonsmoking subjects underwent magnetic resonance imaging (MRI) during 20 min of breathing different oxygen concentrations through a face mask [normoxia, inspired O(2) fraction (Fi(O(2))) = 0.21; hypoxia, Fi(O(2)) = 0.125; hyperoxia, Fi(O(2)) = 0.30] in balanced order. Data were acquired on a 1.5-T MRI scanner during a breath hold at functional residual capacity from both coronal and sagittal slices in the right lung. Arterial spin labeling was used to quantify the spatial distribution of pulmonary blood flow in milliliters per minute per cubic centimeter and fast low-angle shot to quantify the regional proton density, allowing perfusion to be expressed as density-normalized perfusion in milliliters per minute per gram. Neither mean proton density [hypoxia, 0.46(0.18) g water/cm(3); normoxia, 0.47(0.18) g water/cm(3); hyperoxia, 0.48(0.17) g water/cm(3); P = 0.28] nor mean density-normalized perfusion [hypoxia, 4.89(2.13) ml x min(-1) x g(-1); normoxia, 4.94(1.88) ml x min(-1) x g(-1); hyperoxia, 5.32(1.83) ml x min(-1) x g(-1); P = 0.72] were significantly different between conditions in either imaging plane. Similarly, perfusion heterogeneity as measured by relative dispersion [hypoxia, 0.74(0.16); normoxia, 0.74(0.10); hyperoxia, 0.76(0.18); P = 0.97], fractal dimension [hypoxia, 1.21(0.04); normoxia, 1.19(0.03); hyperoxia, 1.20(0.04); P = 0.07], log normal shape parameter [hypoxia, 0.62(0.11); normoxia, 0.72(0.11); hyperoxia, 0.70(0.13); P = 0.07], and geometric standard deviation [hypoxia, 1.88(0.20); normoxia, 2.07(0.24); hyperoxia, 2.02(0.28); P = 0.11] was also not different. We conclude that HPV does not affect pulmonary perfusion heterogeneity in normoxia in the normal supine human lung.

Attentional activation of the cerebellum independent of motor involvement.

The cerebellum traditionally has been viewed as a neural device dedicated to motor control. Although recent evidence shows that it is involved in nonmotor operations as well, an important question is whether this involvement is independent of motor control and motor guidance. Functional magnetic resonance imaging was used to demonstrate that attention and motor performance independently activate distinct cerebellar regions. These findings support a broader concept of cerebellar function, in which the cerebellum is involved in diverse cognitive and noncognitive neurobehavioral systems, including the attention and motor systems, in order to anticipate imminent information acquisition, analysis, or action.

Involvement of striate and extrastriate visual cortical areas in spatial attention.

We investigated the cortical mechanisms of visual-spatial attention while subjects discriminated patterned targets within distractor arrays. Functional magnetic resonance imaging (fMRI) was used to map the boundaries of retinotopic visual areas and to localize attention-related changes in neural activity within several of those areas, including primary visual (striate) cortex. Event-related potentials (ERPs) and modeling of their neural sources, however, indicated that the initial sensory input to striate cortex at 50-55 milliseconds after the stimulus was not modulated by attention. The earliest facilitation of attended signals was observed in extrastriate visual areas, at 70-75 milliseconds. We hypothesize that the striate cortex modulation found with fMRI may represent a delayed, re-entrant feedback from higher visual areas or a sustained biasing of striate cortical neurons during attention. ERP recordings provide critical temporal information for analyzing the functional neuroanatomy of visual attention.

A model for the coupling between cerebral blood flow and oxygen metabolism during neural stimulation.

A general mathematical model for the delivery of O2 to the brain is presented, based on the assumptions that all of the brain capillaries are perfused at rest and that all of the oxygen extracted from the capillaries is metabolized. The model predicts that disproportionately large changes in blood flow are required in order to support small changes in the O2 metabolic rate. Interpreted in terms of this model, previous positron emission tomography (PET) studies of the human brain during neural stimulation demonstrating that cerebral blood flow (CBF) increases much more than the oxygen metabolic rate are consistent with tight coupling of flow and oxidative metabolism. The model provides a basis for the quantitative interpretation of functional magnetic resonance imaging (fMRI) studies in terms of changes in local CBF.

Measurement of end-capillary PO2 with positron emission tomography.

The analysis of positron emission tomography measurements of oxygen metabolism has been extended to provide a quantitative estimate of end-capillary PO2. The principle of this extension rests on the idea that the oxygen extraction fraction can be used to calculate the end-capillary oxygen saturation of the blood. The relation between oxygen saturation and PO2 is obtained through the oxygen dissociation curve. Our studies show that in addition to the local oxygen extraction fraction, arterial PO2 and pH values are needed in the calculation, whereas fairly large variations in factors such as PCO2, hematocrit, hemoglobin, and plasma protein levels have little or no effect. Rough estimates of end-capillary PO2 can be made using standard O2 dissociation nomograms. Blood gas and acid-base properties of blood have been known for decades, making it possible to account accurately for individual differences that may be encountered when studying patients. Measurements in nine normal subjects yielded a mean end-capillary PO2 value of 31.2 mm Hg. The ability to make a quantitative visualization of altered patterns of end-capillary PO2 provides an additional dimension to the investigation of stroke disease and tumor metabolism.

Analysis of some errors in the measurement of oxygen extraction and oxygen consumption by the equilibrium inhalation method.

Some sources of error in the equilibrium inhalation method for the measurement of oxygen extraction fraction and CMRO2 by positron emission computed tomography scanning have been evaluated by computer simulation. Emphasis has been placed on errors that have not been thoroughly studied in past work. These include effects of random statistical errors, systematic errors in arterial blood radioactivity concentrations, and errors due to perturbations of the equilibrium state, to tissue inhomogeneity, and to subject motion.

Evaluation of the 11CO2 positron emission tomographic method for measuring brain pH. I. pH changes measured in states of altered PCO2.

The 11CO2 method for measuring local brain pH with positron emission tomography (PET) has been experimentally evaluated, testing the adequacy of the kinetic model and the ability of the method to measure changes in brain pH. Plasma and tissue time/activity curves measured during and following continuous inhalation of 11CO2 were fit with a kinetic model that includes effects of tissue pH, blood flow, and fixation of CO2 into compounds other than dissolved gas and bicarbonate ions. For each of ten dogs, brain pH was measured with PET at two values of PaCO2 (range 21-67 mm Hg). The kinetic model fit the data well during both inhalation and washout of the label, with residual root mean square (RMS) deviations of the model from the measurements consistent with the statistical quality of the PET data. Brain pH calculated from the PET data shows a linear variation with log(PaCO2). These results were in good agreement with previously reported measurements of brain pH, both in absolute value and in variation with PCO2. The interpretation of these pH values in normal and pathological states is discussed.

The 15O steady-state method: correction for variation in arterial concentration.

One of the factors limiting the accuracy of the 15O steady-state method for the measurement of regional cerebral blood flow and oxygen metabolism is the requirement that a constant arterial blood concentration be maintained over long periods. A new method has been developed to correct for the variation of the arterial concentration in the C15O2 and 15O2 steady-state inhalation technique. The time course of the arterial activity is obtained by multiple sampling over the study period. The same 15O model as is used in the steady-state method is employed but is solved without assuming equilibrium. Look-up tables are generated to relate flow and oxygen extraction fraction to tissue activity, and from them the regional parameters are estimated. Theory and simulation studies suggest that substantial improvement in accuracy can be obtained with no increase in statistical error. The validity of the method was checked experimentally by making repeated measurements in the same subject after perturbing the gas delivery. The conventional steady-state method showed significantly larger deviations in repeat measurement than did the new method. Thus, it is concluded that the proposed method is superior.

Evaluation of the 11CO2 positron emission tomographic method for measuring brain pH. II. Quantitative pH mapping in patients with ischemic cerebrovascular diseases.

A practical method has been developed that, using 11CO2 and positron emission tomography (PET), computes and maps (a) "effective pH" (pHt), a weighted average of intra- and extracellular pH, and (b) "clearance" (K1), product of blood flow and 11CO2 extraction. This method, together with measurements of cerebral blood flow (CBF) and oxygen extraction fraction (OEF), was applied to 12 patients with cerebral ischemia or stroke. The regional K1 was positively correlated with CBF (n = +0.78). The k1/CBF ratio, representing the extraction fraction ratio of 11CO2 to H2 15O, was negatively correlated with CBF (r = -0.54), suggesting that 11CO2 extraction decreases as flow increases. In five acute stroke patients within 2 days of onset, the injured cortex had lower CBF (20.6 ml/min/100 g), higher OEF (78.1%), and lower pHt (6.96) than the contralateral cortex (CBF = 41.4 ml/min/100 g, OEF = 53.3%, pHt = 7.00), suggesting intracellular acidosis with intact cell membranes. In three stroke patients 5-8 days after onset, the injured cortex had higher CBF (60.9 ml/min/100 g), lower OEF (32.0%), and higher pHt (7.12) than the contralateral cortex (CBF = 45.3 ml/min/100 g, OEF = 58.0%, pHt = 7.06), which suggested an increase in extracellular volume compartment reflecting loss of cell membrane integrity. This method provides information on the regional tissue acid-base status and cell membrane integrity, which may be prognostic of tissue viability.

Measurement of brain pH using 11CO2 and positron emission tomography.

We have examined the feasibility of measuring local brain pH in vivo with 11CO2 and positron emission tomography. In particular, we have addressed two objections that have been raised against this method: the assumed need to estimate local tissue PCO2 and the rapid fixation of 11C in tissue. From a reexamination of the basic theory, we argue that after administration of 11CO2 the time-dependent distribution of 11C between tissue and blood is independent of the distribution of CO2 already in the body, making it unnecessary to estimate local tissue PCO2. Assuming that the blood--brain barrier is impermeable to bicarbonate ions, there will be equal partial pressures of 11CO2 in blood and tissue at equilibrium. To overcome the problem of fixation in the tissue we have developed a kinetic model of the time-dependent distribution of 11C that accounts for regional variations in blood flow, CO2 extraction, pH, and rate of fixation. The values of the model parameters can be estimated from sequential measurements of tissue activity concentration during administration of 11CO2. Tissue pH can then be calculated from one of the parameter values, a measurement of arterial pH, and known constants. Numerical calculations based on the kinetic model with assumed values of the parameters were used to optimize the experimental design. The calculations show that problems with fixation are much less severe with continuous infusion of activity than with bolus administration. During infusion the tissue curve depends strongly on tissue pH but only weakly on the rate of fixation.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep deprivation-induced reduction in cortical functional response to serial subtraction.

Thirteen normal volunteers were studied with fMRI during arithmetic performance after a normal night of sleep and following sleep deprivation (SD). Aims included determining whether the prefrontal cortex (PFC) and the parietal lobe arithmetic areas are vulnerable to the effects of SD. After a normal night of sleep, activation localized to the bilateral PFC, parietal lobes and premotor areas. Following SD, activity in these regions decreased markedly, especially in the PFC. Performance also dropped. Data from the serial subtraction task are consistent with Horne's PFC vulnerability hypothesis but, based on this and other studies, we suggest the localized, functional effects of SD in the brain may vary, in part, with the specific cognitive task.

Blood flow dynamics in the vertebrobasilar system: correlation of a transparent elastic model and MR angiography.

PURPOSE: To describe the flow patterns in a model of the vertebrobasilar artery and use these observations to explain the appearance of the flow on the MR images. METHODS: We created an anatomically precise, transparent elastic model of the human vertebrobasilar artery containing a basilar tip aneurysm and perfused the model with non-Newtonian fluid which has similar rheologic properties to blood. Flow patterns in the vessels were directly observed. MR angiogram images were obtained with commercially available two-dimensional time-of-flight, three-dimensional time-of-flight, and 3-D phase-contrast MR angiographic pulse sequences, and they were correlated with the directly seen flow patterns. Quantitative flow velocity measurements were performed with 2-D cine phase-contrast MR angiography and correlated with the flow measured with an electromagnetic flow meter. RESULTS: Visualization studies showed the dye stream patterns in the vertebrobasilar arteries to be extremely complex and variable. During the MR experiments we found that often the same segment of a vessel could appear very different depending on the pulse sequence. In some instances, the model experiments helped to explain the MR appearance of the vessels. Flow profiles measured with 2-D cine phase contrast were found to be consistent with those measured directly with an electromagnetic flow meter. CONCLUSION: Clear elastic models can be used to duplicate the flow in human cranial vessels and thus provide a unique means to observe these flow patterns directly. The flow patterns helped to explain the variation in appearance of the vessels and the artifacts with different MR angiography pulse sequences. The artifacts depend on both the geometry of the vessel and the flow pattern within it. Two-dimensional cine phase-contrast MR provides temporal flow field information that is directly related to physiological information about flow volumes and velocity patterns.

Flow dynamics in a fatal aneurysm of the basilar artery.

PURPOSE: To examine the flow dynamics in a fatal aneurysm of the basilar artery in humans. METHODS: We made transparent elastic replicas of the vertebrobasilar arteries of an elderly patient who died of a ruptured aneurysm in the basilar artery. Using non-Newtonian fluid, physiological pulsatile flow volumes and profiles, and isobaric dyes and particles, we observed and recorded the slipstreams as they entered the aneurysm while changing relative flow in the vertebral arteries. Finally, we placed clips on the aneurysm, leaving residuals (or dog-ears), and observed the slipstreams. RESULTS: The aneurysm originated laterally from the greater curvature of a tortuous basilar artery, measured 19 x 11 x 12 mm, and had a Murphy's teat at the apex, the rupture site. The neck measured 10 x 4 mm, about the diameter of the basilar artery. Slipstreams joined at the confluence of the vertebral arteries, formed helical flow patterns, and entered the aneurysm violently, striking the apex. They then passed proximally around the sac walls, then centrally, and finally reentered the basilar artery to pass distally. Altering the relative flows in the vertebral arteries could modify and prevent slipstream flow into the aneurysm. When a dog-ear was created by incorrect placement of an aneurysm clip, slipstreams entered only dog-ears that lay distal to the clip. Correctly placed clips excluded the aneurysm from the circulation, but did not return the flow dynamics to normal. CONCLUSION: High-velocity slipstreams strike aneurysms at their rupture site and have an impact on distal but not proximal dog-ears. Modifying relative flow may prevent aneurysmal filling. Further, a knowledge of flow dynamics may allow us to predict which aneurysms are at risk of enlarging and rupturing, and may help guide proper therapy.

MR diffusion imaging of cerebral infarction in humans.

PURPOSE: MR diffusion imaging was performed to investigate changes in water diffusion in patients with cerebral infarction. METHODS: Diffusion maps of the apparent diffusion coefficient (ADC) were created to show local water mobility in the brain tissue in 15 patients. These ADC maps were compared with conventional T2-weighted images. RESULTS: Distinct subregions with different water diffusions were detected, even when the infarcted area appeared homogeneous on a T2-weighted image. The results also show that stroke lesions of the same age can have very different water diffusions. A trend towards an increasing diffusion coefficient in a lesion during the first several days following an acute event was observed in a group of patients imaged at multiple timepoints. CONCLUSION: The measurement of diffusion coefficients in vivo now offers an opportunity for greater understanding of the biophysical changes that occur during the evolution of infarction in humans.

Phase-contrast imaging of the parotid region.

Standard T1- and T2-weighted spin-echo acquisitions were compared with T1- and T2-weighted phase-contrast techniques in a series of 10 consecutive patients with parotid masses to assess the role of phase-contrast methods in the evaluation of lesions in the parotid fossa. Greater tissue-lesion contrast was obtained with phase-contrast methods in nine of 10 cases, allowing improved lesion visualization; however, an increase in lesion detectability was not observed in this series. Standard MR imaging methods are sufficient for imaging the parotid region in most cases, but can be quite time-consuming. Recommended screening of the parotid fossa that optimizes tissue-lesion contrast, lesion detectability, and imaging time is performed by combining a standard T1-weighted acquisition with a T1- or T2-weighted phase-contrast acquisition. Selection of a T1- or T2-weighted phase-contrast acquisition is determined by the T1 characteristics of the lesion.

Preliminary clinical results with low flip angle spin-echo MR imaging of the head and neck.

A new approach for producing primarily T2- and proton-density-weighted MR images in less time than the conventional long TR, long TE imaging is to reduce the TR of a double spin-echo pulse sequence and to also reduce the RF excitation flip angle to minimize the resulting T1 sensitivity. In preliminary studies with a human volunteer and five patients with various diseases of the head and neck, conventional long TR, long TE and short TR, short TE images were compared with short TR, long TE images with reduced flip angles (45 degrees, 30 degrees), which required only 40% of the imaging time of the long TR images. The latter images showed a similar contrast pattern to the conventional T2-weighted image, and contrast-to-noise measurements indicated an increase in contrast between the lesion and nearby tissue when the flip angle was reduced. Furthermore, the maximum contrast/noise per unit imaging time on the short TR, long TE image was comparable to that on the long TR, long TE image. Optimization of the flip angle with short TR allows a substantial reduction in imaging time but with a reduction in multislice capability. This technique will be most useful in areas of complex anatomy where two or more orthogonal imaging planes are required, such as the head and neck.

Putting spatial attention on the map: timing and localization of stimulus selection processes in striate and extrastriate visual areas.

This study investigated the cortical mechanisms of visual-spatial attention in a task where subjects discriminated patterned targets in one visual field at a time. Functional magnetic imaging (fMRI) was used to localize attention-related changes in neural activity within specific retinotopic visual areas, while recordings of event-related brain potentials (ERPs) traced the time course of these changes. The earliest ERP components enhanced by attention occurred in the time range 70-130 ms post-stimulus onset, and their neural generators were estimated to lie in the dorsal and ventral extrastriate visual cortex. The anatomical areas activated by attention corresponded closely to those showing increased neural activity during passive visual stimulation. Enhanced neural activity was also observed in the primary visual cortex (area V1) with fMRI, but ERP recordings indicated that the initial sensory response at 50-90 ms that was localized to V1 was not modulated by attention. Modeling of ERP sources over an extended time range showed that attended stimuli elicited a long-latency (160-260 ms) negativity that was attributed to the dipolar source in area V1. This finding is in line with hypotheses that V1 activity may be modulated by delayed, reentrant feedback from higher visual areas.

Mapping the physiological parameters of articular cartilage with magnetic resonance imaging.

The ability of magnetic resonance imaging (MRI) to visualize the spatial distribution of parameters related to the physiological and structural properties of tissues makes it an ideal tool for the study of articular cartilage. A variety of ingenious MRI methods have been devised to probe the complex composition and biochemistry of normal and degenerate articular cartilage. In this article we review the current status of this research and pose some questions concerning the future directions of articular cartilage research and clinical applications.

19F chemical shift imaging technique to measure intracellular pO2 in vivo using perflubron.

RATIONALE AND OBJECTIVES: There is a linear relation between the T1 relaxation rate of fluorine-19 (19F) of perfluorochemicals (PFCs) and the partial pressure of the oxygen (pO2) dissolved in the PFC. A line scan technique was used to overcome the significant chemical shift and low signal-to-noise ratio (SNR) of in vivo 19F magnetic resonance imaging. This study was designed to determine whether the line scan technique could detect the effect of oxygen on 19F T1. In addition, its ability to detect changes in intracellular pO2 when the inspired gas was raised from 20% to 100% O2 also was investigated. METHODS: The T1 relaxation rate of samples of perflubron emulsion diluted from 3.5% to 70% w/v and equilibrated with N2-O2 gas mixtures (pO2 range = 10-450 mm Hg) was measured using the line scan technique. The gas and emulsion pO2 were measured with a blood gas analyzer. The liver T1 relaxation rate was measured in three rabbits given 5 ml/kg perflubron emulsion 4 and 8 days earlier as they breathed room air and then 100% O2. We used a prototype cylindrical coil double-tuned to hydrogen-1 (1H) and 19F and selected a line through the liver. The scanning parameters yielded a voxel size of 20 x 20 x 15.6 mm. Liver and blood samples were obtained postsacrifice for perflubron concentration measurement. RESULTS: A linear relation between the 19F T1 relaxation rate (1/T1) of the 3.5% w/v emulsion and dissolved pO2 was established with a slope of 0.0033 (sec-1/mm Hg) and a correlation coefficient of .991. As the PFC concentration increased by 1,900%, the slope increased by 21.2%. The 1/T1 for the liver was 0.182 +/- 0.004 sec-1 at baseline. It increased to 0.247 +/- 0.022 sec-1 when rabbits breathed 100% O2 (p = .023), which corresponded to an increase in intracellular pO2 of 19.7 mm Hg. The liver-to-blood PFC concentration ratio was 500:1. CONCLUSION: In vitro measurements with the line scan technique replicated the established linear dependence of 1/T1 on pO2. In vivo measurements indicated a 20-mm Hg increase in intracellular pO2 of liver phagocytes when the inspired gas was changed from 20% to 100% O2.