Dynamic changes of magnetic resonance imaging abnormalities in relation to inflammation and glial responses after photothrombotic cerebral infarction in the rat brain

This investigation analyzed the potential of high-resolution magnetic resonance imaging (MRI) at a field strength of 7T to depict leukocyte infiltration and glial responses after focal cerebral ischemia induced by photothrombotic occlusion of cerebral microvessels. For this purpose we superimposed multiparametric MRI (apparent diffusion coefficient, T2, perfusion-weighted, and gadolinium-DTPA-enhanced T1-weighted imaging) on tissue sections stained for phagocytes and astrocytes and, moreover, assessed the regional distribution of tissue pH and ATP content by invasive biochemical methods. Comparing the histological data with the various MRI parameters, high-resolution MRI did not allow a spatial discrimination between distinct areas of phagocyte accumulation or astroglial scar formation, based on image contrast or even quantitative parameter value differences. However, MRI parameters underwent characteristic changes and differentiated distinct stages of tissue remodeling between days 3 and 14 after photothrombosis. Low apparent diffusion coefficient (ADC) and high T2 values indicated an early stage (3 days) with necrosis and beginning glial activation. Normal ADC and reduced T2 elevation characterized an infarct with advanced glial activation and infiltration of hematogenous cells at 7 days after photothrombosis. Heterogeneous ADC together with T2 elevation reflected a late infarct stage (14 days) when pseudocystic degeneration and scar formation had occurred.     

Hemodynamics and metabolism in stroke-prone spontaneously hypertensive rats before manifestation of brain infarcts.

Genomic screening of hybrids from stroke-prone (SHR-SP) and stroke-resistant spontaneously hypertensive rats (SHR) identified a STR1 locus on the rat chromosome 1, which correlates with the susceptibility to cerebral stroke but not with hypertension. The authors examined whether this genetic abnormality is associated with hemodynamic or metabolic alterations in the brain that can be detected before the manifestation of brain infarction. Starting at 6 weeks of age, SHR-SP were fed with a salt-rich diet to accelerate arterial hypertension. At the age of 12 weeks, animals developed functional symptoms and were age-matched with symptom-negative SHR-SP to differentiate between presymptomatic and postsymptomatic changes. Brains were investigated by multiparametric imaging comprising quantitative double-tracer autoradiography of CBF and cerebral protein synthesis (CPS); bioluminescence imaging of regional ATP, glucose, and lactate content; and umbelliferone fluoroscopic imaging of tissue pH. None of the animals exhibited focal hemodynamic or biochemical abnormalities. In symptom-negative SHR-SP, global CBF was 1.1+/-0.3 mL x g(-1) x min(-1), cortical CPS was 10.1+/-3.1 nmol x g(-1) x min(-1), and cortical ATP, glucose, lactate, and pH levels were in the normal range. In SHR-SP with functional symptoms, ATP, glucose, and lactate levels also were normal, but tissue pH exhibited periventricular alkalosis, CBF was significantly reduced to 0.7+/-0.2 mL x g(-1) x min(-1) (P < 0.001), and cortical CPS was significantly reduced to 6.7+/-2.1 nmol x g(-1) x min(-1) (P < 0.001). The decline in brain perfusion of SHR-SP correlated significantly with both the severity of functional deficits and the decline of protein synthesis. Our observations demonstrate that SHR-SP had already developed functional symptoms before the manifestation of overt brain infarcts and that the symptoms are initiated by a decline in global CBF and cortical CPS. Genetic abnormalities in SHR-SP are associated with a diffuse vascular process that results in global decompensation of blood flow well before the onset of focal brain infarction.     

Dynamic tracking of acute ischemic tissue fates using improved unsupervised ISODATA analysis of high-resolution quantitative perfusion and diffusion data.

High-resolution (200 x 200 x 1,500 microm3) imaging was performed to derive quantitative cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) maps in stroke rats (permanent occlusion) every 30 minutes up to 3 hours after occlusion onset, followed by histology at 24 hours. An improved automated iterative-self-organizing-data-analysis-algorithm (ISODATA) was developed to dynamically track ischemic tissue fate on a pixel-by-pixel basis during the acute phase. ISODATA-resolved clusters were overlaid on the CBF-ADC scatterplots and image spaces. Tissue volume ADC, and CBF of each ISODATA cluster were derived. In contrast to the single-cluster normal left hemisphere (ADC = 0.74 +/- 0.02 x 10(-3) mm2/s, CBF = 1.36 +/- 0.22 mL g(-1)min(-1), mean +/- SD, n = 8), the right ischemic hemisphere exhibited three ISODATA clusters, namely: "normal" (normal ADC and CBF), "ischemic core" (low CBF and ADC), and at-risk "perfusion-diffusion mismatch" (low CBF but normal ADC). At 180 minutes, the mismatch disappeared in five rats (Group I, 180-minute "core" lesion volume = 255 +/- 62 mm3 and 24-hour infarct volume = 253 +/- 55 mm3, P > 0.05), while a substantial mismatch persisted in three rats (Group II, 180-minute CBF-abnormal volume = 198 +/- 7 mm3 and 24-hour infarct volume 148 +/- 18 mm3, P < 0.05). The CBF (0.3 +/- 0.09 mL g(-1)min(-1)) of the "persistent mismatch" (Group II, 0.3 +/- 0.09 mL g(-1)min(-1)) was above the CBF viability threshold (0.2 to 0.3 mL g(-1)min(-1)) throughout and its ADC (0.70 +/- 0.03 x 10(-3) mm2/s) did not decrease as ischemia progressed. In contrast, the CBF (0.08 +/- 0.03 mL g(-1)min(-1)) of the analogous brain region in Group I was below the CBF viability threshold, and its ADC gradually decreased from 0.63 +/- 0.05 to 0.43 +/- 0.03 x 10(-3) mm2/s (ADC viability threshold = 0.53 +/- 0.02 x 10(-3) mm2/s). The modified ISODATA analysis of the ADC and CBF tissue characteristics during the acute phase could provide a useful and unbiased means to characterize and predict tissue fates in ischemic brain injury and to monitor therapeutic intervention.     

Pixel-by-pixel spatiotemporal progression of focal ischemia derived using quantitative perfusion and diffusion imaging.

Pixel-by-pixel spatiotemporal progression of focal ischemia (permanent occlusion) in rats was investigated using quantitative perfusion and diffusion magnetic resonance imaging every 30 minutes for 3 hours. The normal left-hemisphere apparent diffusion coefficient (ADC) was 0.76 +/- 0.03 x 10(-3) mm(2)/s and CBF was 0.7 +/- 0.3 mL x g(-1) x min(-1) (mean +/- SD, n=5). The ADC and CBF viability thresholds yielding the lesion volumes (LV) at 3 hours that best approximated the 2,3,5-triphenyltetrazolium chloride (TTC) infarct volumes (200 +/- 30 mm(3)) at 24 hours were 0.53 +/- 0.02 x 10(-3) mm(2)/s (30% +/- 2% reduction) and 0.30 +/- 0.09 mL x g(-1) x min(-1) (57% +/- 11% reduction), respectively. Temporal evolution of the ADC- and CBF-defined LV showed a significant "perfusion-diffusion mismatch" up to 2 hours (P < 0.05, n = 11), a potential therapeutic window. Based on the viability thresholds, three pixel clusters were identified on the CBF-ADC scatterplots: (1) a "normal" cluster with normal CBF and ADC, (2) an "ischemic core" cluster with markedly reduced CBF and ADC, and (3) a "mismatch" cluster with reduced CBF but slightly reduced ADC. These clusters were color-coded and mapped onto the image and CBF-ADC spaces. Lesions grew peripheral and medial to the initial ADC abnormality. In contrast to the CBF distribution, the ADC distribution in the ischemic hemisphere was bimodal; the relatively time-invariant bimodal-ADC minima were 0.57 +/- 0.02 x 10(-3) mm(2)/s (corresponding CBF 0.35 +/- 0.04 mL x g(-1) x min(-1)), surprisingly similar to the TTC-derived thresholds. Together, these results illustrate an analysis approach to systemically track the pixel-by-pixel spatiotemporal progression of acute ischemic brain injury.     

Clinical and radiological correlates of reduced cerebral blood flow measured using magnetic resonance imaging

BACKGROUND: Methods for determining cerebral blood flow (CBF) using bolus-tracking magnetic resonance imaging (MRI) have recently become available. Reduced apparent diffusion coefficient (ADC) values of brain tissue are associated with reductions in regional CBF in animal stroke models. OBJECTIVES: To determine the clinical and radiological features of patients with severe reductions in CBF on MRI and to analyze the relationship between reduced CBF and ADCs in acute ischemic stroke. DESIGN: Case series. SETTING: Referral center. METHODS: We studied 17 patients with nonlacunar acute ischemic stroke in whom perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) were performed within 7 hours of symptom onset. A PWI-DWI mismatch of more than 20% was required. We compared patients with ischemic lesions that had CBF of less than 50% relative to the contralateral hemisphere with patients with lesions that had relative CBF greater than 50%. Characteristics analyzed included age, time to MRI, baseline National Institutes of Health Stroke Scale score, mean ADC, DWI and PWI lesion volumes, and 1-month Barthel Index score. RESULTS: Patients with low CBF (n = 5) had lower ADC values (median, 430 x 10 (-6) mm(2)/s vs. 506 x 10 (-6) mm(2)/s; P =.04), larger DWI volumes (median, 41.8 cm(3) vs. 14.5 cm(3); P =.001) and larger PWI lesions as defined by the mean transit time volume (median, 194.6 cm(3) vs. 69.3 cm(3); P =.01), and more severe baseline National Institutes of Health Stroke Scale scores (median, 15 vs. 9; P =.02). CONCLUSION: Ischemic lesions with severe CBF reductions, measured using bolus-tracking MRI, are associated with lower mean ADCs, larger DWI and PWI volumes, and higher National Institutes of Health Stroke Scale scores.     

Spectacular shrinking deficit: insights from multimodal magnetic resonance imaging after embolic middle cerebral artery occlusion in Sprague-Dawley rats.

Almost no data is available on the serial changes in the brain after spectacular shrinking deficit (SSD) that may help understand this relatively rare clinical phenomenon. Quantitative diffusion-(DWI), perfusion-(PWI), T(1)-(T1WI), T(2)-weighted (T2WI), and functional magnetic resonance imaging (fMRI) were performed before, during, and up to 7 days after embolic middle cerebral artery occlusion (eMCAO) in male Sprague-Dawley rats (n=9). Region of interest (ROI) analysis was used to evaluate structural and functional MR signal changes within three ROIs defined by the apparent diffusion coefficient (ADC), cerebral blood flow (CBF) signatures, and final tissue viability. DWI, PWI, and T2WI lesion volumes were calculated using previously established viability thresholds and final infarct volumes ascertained with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Serial MRI demonstrated spontaneous reperfusion of initially hypoperfused MCA regions accompanied by substantial reduction of initial ADC and CBF lesions and gradual recovery of neurological outcome. Recovery rates of CBF/ADC abnormalities differed among ROIs. Functional magnetic resonance imaging showed persistent tissue dysfunction after the recovery of the CBF/ADC lesions. This study may facilitate our understanding of the pathophysiological mechanisms by which early, spontaneous reperfusion affects tissue fate and neurological function.     

Relation of apparent diffusion coefficient changes and metabolic disturbances after 1 hour of focal cerebral ischemia and at different reperfusion phases in rats.

Changes in apparent diffusion coefficients (ADC) were compared with alterations of adenosine triphosphate (ATP) concentration and pH in different phases of transient focal cerebral ischemia to study the ADC threshold for breakdown of energy metabolism and tissue acidosis during ischemia and reperfusion. Male Wistar rats underwent 1 hour of middle cerebral artery occlusion without recirculation (n = 3) or with 1 hour (n = 4) or 10 hours of reperfusion (n=5) inside the magnet, using a remotely controlled thread occlusion model. ADC maps were calculated from diffusion-weighted images and normalized to the preischemic value to obtain relative ADC maps. Hemispheric lesion volume (HLV) was determined on the last relative ADC maps at different relative ADC thresholds and was compared to the HLV measured by ATP depletion and by tissue acidosis. The HLVs, defined by ATP depletion and tissue acidosis, were 26.0% +/- 10.6% and 38.1% +/- 6.5% at the end of ischemia, 3.3% +/- 2.4% and 4.8% +/- 3.5% after 1 hour of reperfusion, and 11.2% +/- 4.7% and 10.9% +/- 5.2% after 10 hours of recirculation, respectively. The relative ADC thresholds for energy failure were consistently approximately 77% of the control value in the three different groups. The threshold for tissue acidosis was higher at the end of ischemia (86% of control) but was similar to the results obtained for ATP depletion after 1 hour (78% of control) and 10 hours (76% of control) of recirculation. These results indicate that the described relative ADC threshold of approximately 77% of control provides a good estimate for the breakdown of energy metabolism not only during middle cerebral artery occlusion but also at the early phase of reperfusion, when recovery of energy metabolism is expected to occur, or some hours later, when development of secondary energy failure was described.     

Statistical prediction of tissue fate in acute ischemic brain injury.

An algorithm was developed to statistically predict ischemic tissue fate on a pixel-by-pixel basis. Quantitative high-resolution (200 x 200 microm) cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) were measured on acute stroke rats subjected to permanent middle cerebral artery occlusion and an automated clustering (ISODATA) technique was used to classify ischemic tissue types. Probability and probability density profiles were derived from a training data set (n=6) and probability maps of risk of subsequent infarction were computed in another group of animals (n=6) as ischemia progressed. Predictions were applied to overall tissue fate. Performance measures (sensitivity, specificity, and receiver operating characteristic) showed that prediction made based on combined ADC+CBF data outperformed those based on ADC or CBF data alone. At the optimal operating points, combined ADC+CBF predicted tissue infarction with 86%+/-4% sensitivity and 89%+/-6% specificity. More importantly, probability of infarct (P(I)) for different ISODATA-derived ischemic tissue types were also computed: (1) For the 'normal' cluster in the ischemic right hemisphere, P(I) based on combined ADC+CBF data (P(I)[ADC+CBF]) accurately reflected tissue fate, whereas P(I)[ADC] and P(I)[CBF] overestimated infarct probability. (2) For the 'perfusion-diffusion mismatch' cluster, P(I)[ADC+CBF] accurately predicted tissue fate, whereas P(I)[ADC] underestimated and P(I)[CBF] overestimated infarct probability. (3) For the core cluster, P(I)[ADC+CBF], P(I)[ADC], and P(I)[CBF] prediction were high and similar ( approximately 90%). This study shows an algorithm to statistically predict overall, normal, ischemic core, and 'penumbral' tissue fate using early quantitative perfusion and diffusion information. It is suggested that this approach can be applied to stroke patients in a computationally inexpensive manner.     

Late reversal of cerebral perfusion and water diffusion after transient focal ischemia in rats.

Region-specific cerebral blood flow (CBF) and the apparent diffusion coefficient (ADC) of tissue water in the rat brain were quantified by high-field magnetic resonance imaging at 9.4 T in the rat suture occlusion model. Cerebral blood flow and ADC were compared during the short- (4.5 hours) and long-term (up to 6 days) reperfusion after 80 minutes of transient middle cerebral artery occlusion, and correlated with the histology analysis. On occlusion, average CBF fell from approximately 100 to less than 50 mL x 100 g(-1) x min(-1) in the cortex, and to less than 20 mL x 100 g(-1) x min(-1) in the caudate putamen (CP). Corresponding ADC values decreased from (6.98 +/- 0.82) x 10(-4) to (5.49 +/- 0.54) x 10(-4) mm2/s in the cortex, and from (7.16 +/- 0.58) x 10(-4) to (4.86 +/- 0.62) x 10(-4) mm2/s in the CP. On average, CBF recovered to approximately 50% of baseline in the first 24 hours of reperfusion. After 2 to 4 days, a strong hyperperfusion in the ipsilateral cortex and CP, up to approximately 300 mL x 100 g(-1) x min(-1), was observed. The ADC ratio in the ipsilateral and contralateral CP was also inverted in the late reperfusion period. Histology revealed more severe tissue damage at the late stage of reperfusion than at 4.5 hours. Significant reversal of CBF and ADC during the late reperfusion period may reflect the impairment of autoregulation in the ischemic regions. Vascular factors may play an important role in the infarct development after 80-minute focal ischemia.     

Effects of reperfusion on ADC and CBF pixel-by-pixel dynamics in stroke: characterizing tissue fates using quantitative diffusion and perfusion imaging.

The effects of reperfusion on the spatiotemporal dynamics of transient (60 minutes) focal ischemic brain injury in rats were evaluated on a pixel-by-pixel basis using quantitative cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) measurements every 30 minutes for 3 hours and compared to post-mortem histology at 24 hours. Four biologically relevant clusters were classified based on ADC (0.53 +/- 0.02 x 10mm/s, SD) and CBF (0.30 +/- 0.09 ml/g/min) viability thresholds, namely: (1) the "normal" cluster with ADC and CBF > thresholds; (2) the "mismatch" cluster with ADC > threshold but CBF < threshold; (3) the "core" cluster with ADC and CBF < thresholds; and (4) "non-nourishing reperfusion zone" where ADC < threshold but CBF > threshold. The spatio-temporal progression of tissue volumes, ADC and CBF of each cluster were evaluated. Pixels of each cluster on the CBF-ADC space were mapped onto the image space. Following reperfusion, 28% of the "core" pixels and 90% of the "mismatch" (defined at 60 minutes) pixels were salvaged at 180 minutes, which correlated with histology. The ADC and CBF of subsequently salvaged tissues were significantly higher than those became infarcted. Salvaging "core" pixels indicated that reduced ADC was not synonymous with irreversible injury; duration of exposure and severity of reduced ADC and CBF were likely critical. Projection profiles showed a bimodal ADC, but uni-modal CBF, distributions. The ADC bimodal minima, obtained without histological correlation, were similar to the histology-derived ADC and CBF viability thresholds, and could have potential clinical applications. This study demonstrated a simple but powerful approach to evaluate, on a pixel-by-pixel basis, the spatio-temporal evolution of ischemic brain injury, and a potential for statistical prediction of tissue fate.     

Reperfusion after severe local perfusion deficit precedes hemorrhagic transformation: an MRI study in acute stroke patients

BACKGROUND: We applied magnetic resonance imaging to analyze the degree of local diffusion and perfusion abnormalities and the status of reperfusion in regions with subsequent hemorrhagic transformation (HT). METHODS: 51 patients with acute ischemic stroke were studied by diffusion- and perfusion-weighted imaging within 3.0 +/- 0.8 h, on day 1 and days 5-8. After realignment of the image data sets, the parameter maps of the apparent diffusion coefficient (ADC), cerebral blood flow (CBF) and cerebral blood volume (CBV), and mean transit time were analyzed in the area of subsequent HT. The degree of local diffusion and perfusion impairment in the HT area was compared with the entire diffusion and perfusion abnormality. Reperfusion status was separately assessed for the entire perfusion abnormality and the HT area. RESULTS: HT was observed in 19/51 patients (37.2%) within 8 days after symptom onset. Areas destined for HT revealed a more severe decrease in ADC (to 70 +/- 13%; p < 0.01), CBV (to 31 +/- 26%; p < 0.001) and CBF (to 28 +/- 19%; p < 0.001) compared to the entire perfusion abnormality. Local reperfusion in the HT area was seen in 18/19 patients. The presence of HT did not coincide with a worse clinical outcome. DISCUSSION: HT is the result of reperfusion in the region with the most severe local perfusion impairment and does not influence the neurological outcome.     

Cerebral blood flow, glucose utilization, regional glucose, and ATP content during the maturation period of delayed ischemic injury in gerbil brain

Coupling between local perfusion and metabolism was examined in Mongolian gerbils during the development of delayed neuronal death using a combination of double-tracer autoradiography and imaging of local energy state. Animals were anesthetized with 1.5% halothane and forebrain ischemia was produced by occluding both common carotid arteries. After 5 min of ischemia, brains were recirculated for 6 h and 1, 2, or 4 days. At the end of the experiment, regional cerebral blood flow (CBF) and glucose utilization (CMRglc) were determined in identical brain section with [131I]iodoantipyrine and [14C]deoxyglucose, respectively. Adjacent sections were taken for imaging of ATP and glucose using substrate-specific bioluminescence reactions. In the CA1 subfield of control animals, CBF and CMRglc amounted to 81 +/- 8 ml 100 g-1min-1 and 69 +/- 2 mumol 100 g-1min-1, respectively, and the calculated CBF/CMRglc ratio was 1.18 +/- 0.12 ml/mumol (mean +/- SD). After ischemia, the CBF/CMRglc ratio increased to 1.31 +/- 0.14, 1.43 +/- 0.16, 1.45 +/- 0.16, and 1.56 +/- 0.18 ml/mumol following 6 h and 1, 2, or 4 days recirculation, respectively. Glucose levels did not change during the 6 h to 4 day recirculation period in the hippocampal CA1 subfield. In the same region, ATP levels were unchanged during 6 h to 2 day postischemic recovery but reduced to about 70% after 4 days of recirculation. The results indicate that a mismatch of the flow--metabolism couple following transient ischemia does not appear to contribute to the postischemic maturation of delayed neuronal death in selectively vulnerable brain regions.     

Delayed rt-PA treatment in a rat embolic stroke model: diagnosis and prognosis of ischemic injury and hemorrhagic transformation with magnetic resonance imaging.

The authors characterized effects of late recombinant tissue plasminogen activator (rt-PA) administration in a rat embolic stroke model with magnetic resonance imaging (MRI), to assess potential MRI correlates, or predictors, or both, of rt-PA-induced hemorrhage. Diffusion-, perfusion-, and postcontrast T1-weighted MRI were performed between 4 and 9 hours and at 24 hours after embolic stroke in spontaneously hypertensive rats. Treatment with either rt-PA or saline was started 6 hours after stroke. A spectrophotometric hemoglobin assay quantified hemorrhage severity. Before treatment, relative cerebral blood flow index (rCBFi) and apparent diffusion coefficient (ADC) in the ischemic territory were 30% +/- 23% and 60% +/- 5% (of contralateral), respectively, which increased to 45% +/- 39% and 68% +/- 4% 2 hours after rt-PA. After 24 hours, rCBFi and ADC were 27% +/- 27% and 59 +/- 5%. Hemorrhage volume after 24 hours was significantly greater in rt-PA-treated animals than in controls (8.7 +/- 3.7 microL vs. 5.1 +/- 2.4 microL, P < 0.05). Before rt-PA administration, clear postcontrast T1-weighted signal intensity enhancement was evident in areas of subsequent bleeding. These areas had lower rCBFi levels than regions without hemorrhage (23% +/- 22% vs. 36% +/- 29%, P < 0.05). In conclusion, late thrombolytic therapy does not necessarily lead to successful reperfusion. Hemorrhage emerged in areas with relatively low perfusion levels and early blood-brain barrier damage. Magnetic resonance imaging may be useful for quantifying effects of thrombolytic therapy and predicting risks of hemorrhagic transformation.     

Artificial neural network prediction of ischemic tissue fate in acute stroke imaging

Multimodal magnetic resonance imaging of acute stroke provides predictive value that can be used to guide stroke therapy. A flexible artificial neural network (ANN) algorithm was developed and applied to predict ischemic tissue fate on three stroke groups: 30-, 60-minute, and permanent middle cerebral artery occlusion in rats. Cerebral blood flow (CBF), apparent diffusion coefficient (ADC), and spin–spin relaxation time constant (T2) were acquired during the acute phase up to 3 hours and again at 24 hours followed by histology. Infarct was predicted on a pixel-by-pixel basis using only acute (30-minute) stroke data. In addition, neighboring pixel information and infarction incidence were also incorporated into the ANN model to improve prediction accuracy. Receiver-operating characteristic analysis was used to quantify prediction accuracy. The major findings were the following: (1) CBF alone poorly predicted the final infarct across three experimental groups; (2) ADC alone adequately predicted the infarct; (3) CBF+ADC improved the prediction accuracy; (4) inclusion of neighboring pixel information and infarction incidence further improved the prediction accuracy; and (5) prediction was more accurate for permanent occlusion, followed by 60- and 30-minute occlusion. The ANN predictive model could thus provide a flexible and objective framework for clinicians to evaluate stroke treatment options on an individual patient basis.     

Dynamic imaging of perfusion and oxygenation by functional magnetic resonance imaging.

Cerebral blood flow can be measured with magnetic resonance imaging (MRI) by arterial spin labeling techniques, where magnetic labeling of flowing spins in arterial blood water functions as the endogenous tracer upon mixing with the unlabeled stationary spins of tissue water. The consequence is that the apparent longitudinal relaxation time (T1) of tissue water is attenuated. A modified functional MRI scheme for dynamic CBF measurement is proposed that depends on extraction of T1 weighting from the blood oxygenation level-dependent (BOLD) image contrast, because the functional MRI signal also has an intrinsic T1 weighting that can be altered by variations of the excitation flip angle. In the alpha-chloralose-anesthetized rat model at 7T, the authors show that the stimulation-induced BOLD signal change measured with two different flip angles can be combined to obtain a T1-weighted MRI signal, reflecting the magnitude of the CBF change, which can be deconvolved to obtain dynamic changes in CBF. The deconvolution of the T1-weighted MRI signal, which is a necessary step for accurate reflection of the dynamic changes in CBF, was made possible by a transfer function obtained from parallel laser-Doppler flowmetry experiments. For all stimulus durations (ranging from 4 to 32 seconds), the peak CBF response measured by MRI after the deconvolution was reached at 4.5 +/- 1.0 seconds, which is in good agreement with (present and prior) laser-Doppler measurements. Because the low flip angle data can also provide dynamic changes of the conventional BOLD image contrast, this method can be used for simultaneous imaging of CBF and BOLD dynamics.     

Heterogeneous oxygen extraction in the visual cortex during activation in mild hypoxic hypoxia revealed by quantitative functional magnetic resonance imaging.

Functional magnetic resonance imaging (fMRI) techniques were used to study haemodynamic and metabolic responses in human visual cortex during varying arterial blood oxygen saturation levels (Y(sat), determined by pulse-oximeter) and stimulation with contrast-reversing checkerboards. The visual-evoked potential amplitude remained constant at lowered Y(sat) of 0.82+/-0.03. Similarly, fMRI cerebral blood flow (CBF) responses were unchanged during reduced Y(sat). In contrast, visual cortex volume displaying blood oxygen level-dependent (BOLD) fMRI response decreased as a function of Y(sat), but the BOLD signal change of 3.6%+/-1.4% was constant. Oxygen extraction ratio (OER) during visual activation showed values of 0.26+/-0.03 for normal Y(sat). At lowered Y(sat), two OER patterns were observed. Firstly, a reduced OER of 0.14+/-0.03 in the visual cortex structures showing BOLD in hypoxia was observed. Secondly, signs of much higher OER in other parts of visual cortex were obtained. T2*-weighted magnetic resonance imaging revealed signal increases by 0.8%+/-0.4% with visual activation during lowered Y(sat) in the visual cortex structures, which showed BOLD of 3.6% in magnitude under normoxia. Because the CBF response in the visual cortex was quantitatively similar during stimulation in normoxia and hypoxia, attenuated T2*-weighted signal increase in parts of visual cortex indicated high OER during visual activation in hypoxia, which was close to that encountered in the resting brain. These spatially localised regions of tissue oxygen extraction and metabolism argue for dissociation between CBF and BOLD fMRI signals in mild hypoxia. The findings point to heterogeneity with regard to oxygen requirement and its coupling to the haemodynamic response in the brain.     

A multiparametric assessment of oxygen efflux from the brain.

A quantitative understanding of unidirectional versus net extraction of oxygen in the brain is required because an important factor in calculating oxidative metabolism by calibrated functional magnetic resonance imaging (fMRI) as well as oxygen inhalation methods of positron emission tomography (15O2-PET) and nuclear magnetic resonance (17O2-NMR)) is the degree of oxygen efflux from the brain back into the blood. Because mechanisms of oxygen transport from blood to brain are dependent on cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), and oxygen partial pressure (pO2) values in intravascular (Piv) and extravascular (Pev) compartments, we implemented multimodal measurements of these parameters into a compartmental model of oxygen transport and metabolism (i.e., hemoglobin-bound oxygen, oxygen dissolved in plasma and tissue spaces, oxygen metabolized in the mitochondria). In the alpha-chloralose anesthetized rat brain, we used magnetic resonance (7.0 T) and fluorescence quenching methods to measure CMRO2 (2.5+/-1.0 micromol/g min), CBF (0.7+/-0.2 mL/g min), Piv (74+/-10 mm Hg), and Pev (16+/-5 mm Hg) to estimate the degree of oxygen efflux from the brain. In the axially distributed compartmental model, oxygen molecules in blood had two possible fates: enter the tissue space or remain in the same compartment; while in tissue there were three possible fates: enter the blood or the mitochondrial space, or remain in the same compartment. The multiparametric results indicate that the probability of unmetabolized (i.e., dissolved) oxygen molecules reentering the blood from the tissue is negligible and thus its inclusion may unnecessarily complicate calculations of CMRO2 for 15O-PET, 17O-NMR, and calibrated fMRI methods.     

Diffusion-weighted MR imaging and pathologic findings in adult cerebellar medulloblastoma

OBJECTIVES, MATERIALS AND METHODS: The authors present the diffusion-weighted MR imaging and pathologic findings in two adult patients with cerebellar medulloblastoma. RESULTS: Both presented with a vermian mass of the posterior fossa with low signal on SE T1 weighted images, and moderate enhancement of the mass after gadolinium injection. The tumors were of high intensity on diffusion-weighted images with low ADC value. The ADC values (x10(-3) mm2/s) were respectively 0.60 +/- 0.06 and 0.59+/-0.11 (tumor), and 0.65 +/- 0.04 and 0.67 +/- 0.07 (cerebellar white matter). Tumors were highly cellular and composed of densely packed small round cells with hyperchromatic nuclei and scanty cytoplasm. CONCLUSION: diffusion-weighted MR imaging may be useful for the diagnosis of cerebellar medulloblastoma, due to their high cellularity and high nuclear-to-cytoplasmic ratio.     

Contrast-enhanced perfusion and diffusion MRI accurately lateralize temporal lobe epilepsy: a pilot study.

AIMS: To undertake a pilot study to assess whether magnetic resonance (MR) contrast-enhanced perfusion imaging (CEPI) and diffusion-weighted imaging (DWI) provide lateralizing information in medically refractory temporal lobe epilepsy (TLE),and to compare this to standard quantitative hippocampal assessments (volumetric measurements and T2 relaxometry). METHODS: Ten patients with 'non-lesional' TLE and 10 control subjects were studied. Quantification of the relative cerebral blood flow (rCBF) and apparent diffusion coefficient (ADC) was performed for the hippocampal regions. The ratios of the ipsilateral-to-contralateral side (to the EEG lateralization) were compared with the side-to-side ratios in the controls. RESULTS: Six patients (60%) had an ADC ratio outside the control range (the larger ADC ipsilateral to the EEG lateralization in all cases). The CBF ratios were outside the control range in all eight patients (100%) in whom CEPI was performed (the lower value ipsilateral to the EEG lateralization in all cases). The magnitude of the hippocampal volume (HV) ratios showed no significant correlation with the magnitude of the ADC ratios (R=-0.03, p=0.93) or CBF ratios (R=0.36, p=0.39). There was a closer relationship with the T2 relaxometry ratios, but this was also not significant (R=-0.40, p=0.32; R=0.58, p=0.08). CONCLUSIONS: DWI and CEPI show potential as reliable tools for the lateralization of non-lesional TLE. Further studies with larger numbers are necessary to determine whether these techniques provide independent data to established MR quantitative measures.     

Quantitative assessment of the balance between oxygen delivery and consumption in the rat brain after transient ischemia with T2 -BOLD magnetic resonance imaging.

The balance between oxygen consumption and delivery in the rat brain after exposure to transient ischemia was quantitatively studied with single-spin echo T2-BOLD (blood oxygenation level-dependent) magnetic resonance imaging at 4.7 T. The rats were exposed to graded common carotid artery occlusions using a modification of the four-vessel model of Pulsinelli. T2, diffusion, and cerebral blood volume were quantified with magnetic resonance imaging, and CBF was measured with the hydrogen clearance method. A transient common carotid artery occlusion below the CBF value of approximately 20 mL x 100 g(-1) x min(-1) was needed to yield a T2 increase of 4.6 +/- 1.2 milliseconds (approximately 9% of cerebral T2) and 6.8 +/- 1.7 milliseconds (approximately 13% of cerebral T2) after 7 and 15 minutes of ischemia, respectively. Increases in CBF of 103 +/- 75% and in cerebral blood volume of 29 +/- 20% were detected in the reperfusion phase. These hemodynamic changes alone could account for only approximately one third of the T2 increase in luxury perfusion, suggesting that a substantial increase in blood oxygen saturation (resulting from reduced oxygen extraction by the brain) is needed to explain the magnetic resonance imaging observation.