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(Stroke. 1995;26:451-458.)
© 1995 American Heart Association, Inc.

Articles

Combined Perfusion and Diffusion-Weighted Magnetic Resonance Imaging in a Rat Model of Reversible Middle Cerebral Artery Occlusion

Tomm B. Müller, MD; Olav Haraldseth, MD, PhD; Richard A. Jones, PhD; Giovanni Sebastiani, MSc; Fred Godtliebsen, PhD; Christian F. Lindboe, MD, PhD Geirmund Unsgård, MD, PhD

From the MR–Center, SINTEF/UNIMED (T.B.M., O.H., R.A.J.); the Department of Mathematical Sciences, The Norwegian Institute of Technology (G.S., F.G.); and the Departments of Pathology (C.F.L.) and Neurosurgery (G.U.), University Hospital of Trondheim, Trondheim, Norway.

Correspondence to Tomm B. Müller, MR–Center, SINTEF/UNIMED, N–7034 Trondheim, Norway.

	Abstract

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Background and Purpose Diffusion-weighted imaging and dynamic first-pass bolus tracking of susceptibility contrast agents (perfusion imaging) are two new magnetic resonance imaging techniques that offer the possibility of early diagnosis of stroke. The present study was performed to evaluate the diagnostic information derived from these two methods in a rat model of temporary focal ischemia.

Methods Fifteen male Wistar rats were assigned to 45 (n=7) or 120 minutes (n=8) of middle cerebral artery occlusion followed by reperfusion using the intraluminal filament technique. The diffusion-weighted images were collected, and areas of hyperintensity were compared with histologically assessed areas of ischemic injury. The magnetic resonance perfusion image series were postprocessed to produce topographic maps reflecting the maximum reduction in the signal obtained during the first passage of the contrast agent and the time delay between the arrival of the bolus and the point of maximum contrast-agent effect.

Results Hyperintensity in diffusion-weighted images was demonstrated after 30 minutes of middle cerebral artery occlusion and was mainly expressed in the lateral caudoputamen and parts of the lower frontoparietal cortex. Reperfusion after 45 minutes of occlusion reduced the area of hyperintensity from 24.2% to 9.9% of hemispheric area. In the group with 120 minutes of occlusion, the hyperintense area increased from 24.4% to 29.1%. Relative to the nonischemic hemisphere, the changes in the topographic maps of maximum signal reduction occurred in the lateral caudoputamen and adjacent lower neocortical areas. Increased time delay to maximum effect, however, was seen also in the upper frontoparietal cortex.

Conclusions Hyperintensity in diffusion-weighted images was reversible after 45 minutes but not after 120 minutes of middle cerebral artery occlusion. Analysis of the signal-reduction and time-delay parametric maps demonstrated regions of different perfusion changes in the ischemic hemisphere.

Key Words: cerebral ischemia, focal • magnetic resonance imaging • middle cerebral artery • rats

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Two recently developed magnetic resonance (MR) imaging techniques offer the possibility of early diagnosis of thromboembolic stroke in humans. The first of these techniques, dynamic first-pass bolus tracking of susceptibility contrast agents (often referred to as perfusion imaging or perfusion-sensitive imaging), has been used to demonstrate the perfusion reduction in focal ischemia in animal models^{1 2 3 4 5 6} and stroke patients.^{7 8} Tracer kinetic theory has been applied to the resulting images in an attempt to measure hemodynamic parameters such as regional cerebral blood volume or regional cerebral blood flow in exact terms.^{1 3 5 6 8 9 10 11} These methods are, however, controversial in the case of physiological changes in perfusion^{12 13} and even more so with the reduced perfusion and pathophysiology of focal ischemia.⁵ The second imaging technique, diffusion-weighted (DW) MR imaging, is sensi-tive to early tissue damage in animal models of focal cerebral ischemia.^{5 6 14 15 16 17 18} In the case of severe global ischemia, changes in DW images can be observed as early as 2 to 3 minutes after the start of the insult.^{19 20} The hyperintensity in the DW images is caused by a reduction in the translational diffusion of water in the ischemic tissue. There is some experimental evidence that this reduction is related to energy failure^{19 20} and that the hyperintensity is a result of the shift of water from the extracellular to the intracellular space and changes in the extracellular volume.^{21 22} However, the exact pathophysiological mechanisms are not completely understood.^{23 24}

To further explore the potential of these two methods for stroke diagnosis, an MR imaging study of a rat model of reversible middle cerebral artery (MCA) occlusion was performed. In particular, the diagnostic information derived from MR perfusion imaging was evaluated for the ability to show reperfusion and to distinguish between a core area of severe flow reduction and a surrounding area of mild to moderate flow reduction. The relative changes in perfusion during ischemia and early reperfusion were characterized by the use of two simple perfusion parameters calculated from the dynamic perfusion images. The distribution and reversibility of early ischemic tissue injury, as assessed by hyperintensity in the DW images, were studied during both short and long periods of MCA occlusion, followed by reperfusion.

	Materials and Methods

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The surgical procedures were approved by the Norwegian Committee for Animal Experiments. Fifteen male Wistar rats (Møllegaard Breeding Center) weighing between 320 and 350 g were randomly assigned to groups undergoing MCA occlusion of either 45 (n=7) or 120 (n=8) minutes in duration. Anesthesia was induced with isoflurane, and the rats were intubated, connected to a respirator, and ventilated with 1.5% isoflurane in a mixture of 70% nitrogen and 30% oxygen during surgery. Occlusion of the MCA was achieved by the intraluminal filament technique originally described by Koizumi et al²⁵ and later modified by various groups.^{26 27 28} Through a ventral midline neck incision, the right common, external, and internal carotid arteries were isolated. A nylon filament with a diameter of 0.27 mm and a rounded tip was introduced through the external carotid artery and advanced 19 to 20 mm, thus blocking the origin of the MCA. Reperfusion was achieved by retraction of the nylon filament into the external carotid artery. After preparatory surgery, the rats were placed in a home-built animal cradle for MR imaging, and the isoflurane was reduced to 1.0% for the rest of the experiment. During the experiment, intravenous injections of 150 IU/kg heparin (to avoid secondary thrombosis in the MCA) and intramuscular injections of 2 mg/kg pancuronium (for muscle relaxation) were administered at intervals of 1 hour. The right femoral artery and vein were cannulated, and systemic arterial blood pressure was monitored continuously during the experiment. Arterial blood gases were measured before and after ischemia. Rectal temperature was monitored throughout the experiment and maintained between 36.5°C and 37.5°C with a heating blanket during surgery and with heated fluorocarbons circulating in a closed chamber in the animal cradle during the MR imaging. At the end of the experiment, the animals were killed and perfusion-fixed with 4% formalin for histological examination.

To accurately analyze the perfusion via the first passage of a contrast agent through the brain, the frequency of the image acquisition must be high enough for the first passage to be well characterized. As tracer recirculation in rats is rapid, it was decided that subsecond time resolution would be necessary if this criterion were to be fulfilled. The change in image intensity induced by the contrast agent is proportional to the echo time; therefore, extending the echo time improves the contrast for a given dose of contrast agent. Pilot studies showed that an intravenous 1-second bolus of 0.5 mmol/kg Sprodiamide injection (dysporium diethylenetriaminepentaacetic acid-bis[methylamide] [Dy-DTPA-BMA], Nycomed Imaging A/S) and a gradient echo scan with an echo time of 10 milliseconds produced acceptable contrast between the ischemic and normally perfused tissue on our 2.35-T Bruker Biospec system and was used in the perfusion studies described in this article. With an echo time of 10 milliseconds, the minimum repetition time available on our system was 18 milliseconds, resulting in a scan time of 2.4 seconds for a 128x128 image or 1.2 seconds if a 128x64 matrix was used. Further reductions in the number of lines acquired reduced the image quality to an unacceptable extent; techniques such as echo planar imaging cannot be implemented on our system. To achieve a further reduction in the scan time, we developed a k-space substitution technique⁴ in which only the 32 lines covering the low spatial frequencies are acquired for each dynamic image. To reconstruct these images, the 32 lines acquired for each dynamic image are pasted over the corresponding lines in a full 128x128 data set acquired before the dynamic scan. While the 128x128 images thus obtained preserve the contrast changes in the images, there is some degradation of the image resolution because of the lack of dynamically acquired high spatial frequencies. To assess whether this would compromise our ability to observe variations in signal intensity around the ischemic core, a trial study was performed in which a series of seven 128x128 images of a single 3-mm-thick slice located at the optic chiasm was acquired during the injection of a 1-second bolus of 0.5 mmol/kg Sprodiamide, with the bolus arriving at the brain in the course of the third image. These data sets were then reconstructed, both in the standard way and also by using the first image as a reference image and substituting the central 32 lines from each of the following images into the first image before Fourier transformation (ie, k-space substitution). A comparison of the resulting images is shown in Fig 1. There is some loss of detail in the k-space–substituted data; in general, very small, transient features cannot be characterized accurately by k-space substitution. However, our experience is that the compromise that k-space substitution provides between temporal and spatial resolution leads to the best overall assessment of the core and perifocal ischemic lesions and was therefore used for the perfusion studies described in this article.

View larger version (99K): [in this window] [in a new window]   Figure 1. Three of a set of seven 128x128 rat head images acquired during the first passage of a 0.5-mmol/kg bolus of Sprodiamide injection, with a scan time of 2.4 seconds per image, processed in two different ways. The images in the bottom line were reconstructed in the usual manner. For the upper line, the central 32 lines of the initial data set (which correspond to the low spatial frequencies) were replaced by the corresponding lines from each of the other six data sets before reconstruction, ie, k-space substitution. A small loss of detail can be observed in the k-space–substituted data.

The DW imaging was performed with the same slice thickness and field of view (3 mm and 6.4 cm, respectively) as the k-space studies with the midslice positioned at the level of the optic chiasm. The multiple-slice, DW spin-echo sequence used a full 128x128 matrix, an echo time of 68 milliseconds, a repetition time of 1300 milliseconds, and six averages, yielding a scan time of 20 minutes. Applying strong unipolar gradients in the z direction on either side of the refocusing 180 pulse resulted in a b factor of approximately 1400 s/mm².

There were two experimental groups: (1) 120 minutes of MCA occlusion and 120 minutes of reperfusion (n=8) and (2) 45 minutes of MCA occlusion and 70 minutes of reperfusion (n=7). In both groups, single-slice perfusion imaging was performed after 40 minutes of MCA occlusion and after 10 and 60 minutes of reperfusion. DW imaging was performed after 30 minutes of MCA occlusion and after 50 minutes of reperfusion. Additional imaging sequences in the 120-minute MCA occlusion group resulted from perfusion imaging after 100 minutes of MCA occlusion and DW imaging after 90 minutes of MCA occlusion and 100 minutes of reperfusion.

For the bolus tracking images, the curves for signal intensity versus time were processed on a pixel-to-pixel basis. The following two characteristics of the curves were determined after nonparametric linear regression modeling²⁹ and displayed as topographic maps: (1) maximum signal reduction, defined as the maximum reduction in the signal intensity during passage of the bolus, and (2) time delay, defined as the time delay between the arrival of the bolus in the brain and the point of maximum change in the signal intensity.

For the DW images, the area of ischemic tissue injury was calculated as the number of pixels with hyperintensity of 15% relative to the corresponding anatomic structures in the contralateral hemisphere. This figure was then divided by the number of pixels in the hemisphere and expressed as percent of hemispheric lesion area in all three slices as an approximation to volume of ischemic injury. The threshold value of 15% was chosen because it was found to be the lowest cutoff value that did not include pixels in the contralateral nonischemic hemisphere.

To compare DW hyperintensity with histopathologic changes at the time of image acquisition, rats in the group with 120 minutes of MCA occlusion were transcardiac perfusion-fixed with 4% formalin immediately after death. Brains were removed, and 4-µm-thick paraffin sections corresponding to the level of the MR images were cut. The sections were stained with hematoxylin and eosin and were examined by a neuropathologist blinded to the results of the MR imaging. The areas with ischemic injury showed reduced staining intensity and diffuse vacuolization of the neuropil and a widening of the pericellular and perivascular spaces. The changes were only seen in the ipsilateral hemisphere and were well demarcated from adjacent unaffected tissue. The neurons generally showed a dark and shrunken cytoplasm corresponding to so-called "dark neurons," but the survival time was too short for development of the characteristic ischemic nerve cell damage. For the group with 45 minutes of MCA occlusion, the survival time was considered too short for useful histological examination. The sections were digitized, and areas of ischemic injury were calculated as percent of hemispheric lesion area.

The various parameters were compared between the two groups using paired or unpaired Student's t tests, as appropriate. In the case of a regression analysis between two groups, the significance was assessed using an ANOVA analysis of regression.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
There were no significant differences between the two groups in arterial PCO₂, PO₂, pH, or base excess (data not shown). Rectal temperature and systemic arterial pressure are presented in Table 1. Except for a small temporary increase in temperature during MCA occlusion, both systemic arterial pressure and rectal temperature were stable throughout the experiment.

View this table: [in this window] [in a new window]   Table 1. Mean Arterial Pressure and Body Temperature During Middle Cerebral Artery Occlusion and Reperfusion

Six consecutive images with an interval of 0.6 seconds selected from a typical series of 30 images obtained during the first-pass passage of a bolus of Dy-DTPA-BMA through the brain of a rat with an MCA occlusion are presented in Fig 2. As the bolus reaches the brain, the normally perfused tissue turns dark because the susceptibility effect of the contrast agent causes a reduction in signal intensity. The ischemic area in the right hemisphere is seen as a relatively brighter spot. In this animal model, the core and penumbra of the ischemic lesion are typically expressed in the lateral caudoputamen and the upper frontoparietal cortex, respectively.²⁸ Therefore, these two regions were selected for further analysis.

View larger version (84K): [in this window] [in a new window]   Figure 2. Six consecutive transaxial images of a rat head during the first passage of a bolus of Sprodiamide injection. The images were obtained with an interval of 0.6 second. The first image depicts the arrival of the bolus, and the following images are during the first passage of the bolus. The brain is the bright oval at the top of the images. In the left hemisphere (to the right in the images), blood supply is uninterrupted, and the susceptibility effect of the contrast agent reduces signal intensity as the bolus reaches the brain. The ischemic area in the right hemisphere (to the left in the images) is seen as a relatively brighter spot, reflecting the reduced perfusion. The first-pass transit is rapid in the rat brain, and early washout is evident in the last image.

Fig 3 shows typical signal intensity changes during the bolus passage in the selected regions of interest in the ischemic and normal hemispheres. The dynamic imaging sequence covers 18 seconds, with the first passage occurring after approximately 6 seconds. In the nonischemic hemisphere, a well-defined first pass is observed in which the maximum signal reduction is approximately 50%. Subsequently, the signal recovers to 80% of its initial value. Additional studies showed that the signal in the brain recovered to the initial value within 15 minutes with the sequence used in these studies. In the upper frontoparietal cortex of the ischemic hemisphere, the signal reduction followed a similar pattern, but the peak effect was delayed, and the subsequent recovery was somewhat slower, than in the nonischemic hemisphere. In the lateral caudoputamen of the ischemic side, there was no first-pass effect, rather a gradual reduction in the signal. The spatial variations in the dynamics of the first passage of the bolus during ischemia are more easily appreciated after the pixel-to-pixel processing of the dynamic image series to yield topographic maps of maximum signal reduction and time delay to maximum signal reduction. In Fig 4, the topographic maps of signal reduction (Fig 4A) and time delay (Fig 4B) from the rat in Fig 2 are shown. In the signal reduction map, the changes were mainly restricted to the lateral caudoputamen and the adjacent lower parts of cortex, whereas the time delay map demonstrated a larger affected area that also included the upper parts of the neocortex.

View larger version (21K): [in this window] [in a new window]   Figure 3. Typical one-pixel bolus tracking curves from normally perfused brain in the nonischemic hemisphere and the areas of the upper frontoparietal cortex and the lateral caudoputamen in the ischemic hemisphere.

View larger version (67K): [in this window] [in a new window]   Figure 4. Topographic maps calculated from the perfusion images obtained after 40 minutes of middle cerebral artery (MCA) occlusion and reperfusion from the same rat as in Fig 2. Only the brain is shown, and the ischemic right hemisphere is to the left in the images. A, Maximum signal reduction map during MCA occlusion (the smaller the change in signal intensity during passage of the bolus, the darker the pixel); B, time delay map during MCA occlusion (the longer the interval to maximal reduction in signal intensity, the brighter the pixel); C, maximum signal reduction map; and D, time delay map obtained after 60 minutes of reperfusion.

For both perfusion parameters, the relative values compared with the contralateral nonischemic hemisphere were calculated in regions of interest. After 30 minutes of MCA occlusion, the mean relative values in the maximum signal reduction maps were 64% in the ischemic caudoputamen and 82% in the ischemic upper frontoparietal cortex (Fig 5). The time delay was approximately doubled in both regions during the MCA occlusion (Fig 6). During reperfusion, the signal reduction maps did not demonstrate any significant differences between the two hemispheres. However, the time delay maps displayed a persistent asymmetry after reperfusion in both groups (Fig 6). The time delay in reperfusion was not correlated to the severity of the ischemic insult since it was similar in both regions of interest after either 45 or 120 minutes of MCA occlusion.

View larger version (68K): [in this window] [in a new window]   Figure 5. Bar graph showing the maximum signal reduction, as measured in the topographic maps, relative to the contralateral nonischemic side in regions of interest in lateral caudoputamen (cp) and upper frontoparietal cortex (cx) in the two groups during middle cerebral artery occlusion (MCAO) and reperfusion (repf). Values are mean±SD. *Different from upper frontoparietal cortex with P=.03, unpaired Student's t test.

View larger version (59K): [in this window] [in a new window]   Figure 6. Bar graph showing the time delay to maximum signal reduction, as measured in the topographic maps, relative to the contralateral nonischemic side in regions of interest in lateral caudoputamen (cp) and upper frontoparietal cortex (cx) in the two groups during middle cerebral artery occlusion (MCAO) and reperfusion (repf). Values are mean±SD.

A typical hyperintense lesion in the DW images is shown in Fig 7A. The hyperintensity in the DW images was observed in the lateral caudoputamen in all rats, and in some rats the lower cortical areas were also included. In one rat, the hyperintense lesion extended into the upper frontoparietal cortex (Fig 7C). This rat also had a considerably higher signal hyperintensity in the lateral caudoputamen, indicating a more rapidly evolving tissue damage. However, there were no differences in the measured physiological parameters to explain this result, and the rat was included in all of the presented results. The mean area of ischemic injury, as calculated from the middle slice in the DW images, was 38.8±14.3% of hemispheric ipsilateral area compared with 31.6±6.0%, which was the mean area of ischemic injury as determined from a single histological section of a comparable slice at the end of the experiment. Regression analysis showed a significant correlation coefficient of 0.84 (P<.01, F test) between the ischemic area in the histological section and the area of DW hyperintensity.

View larger version (93K): [in this window] [in a new window]   Figure 7. Example of a typical hyperintense lesion in a diffusion-weighted image of a rat in the group with 120 minutes of middle cerebral artery occlusion (A). This can be compared with the area of ischemic injury in the histopathologic section (B, dotted area). In one rat, the hyperintense lesion also included the upper frontoparietal cortex (C); this rat also had the largest area of ischemic injury at histopathologic examination (D). The images were acquired after 100 minutes of reperfusion, and the histological sections were prepared after 120 minutes of reperfusion.

In Table 2, the results from calculations of the total area of DW hyperintensity in all three imaged slices are shown. After 30 minutes of MCA occlusion, the mean size of the areas of hyperintensity was equal in the two groups. However, reestablishing flow after 45 minutes caused a statistically significant reduction in the mean area of DW hyperintensity from 24.2±9.2% during MCA occlusion to 9.9±8.5% of the hemisphere at 50 minutes of reperfusion (P<.005, paired Student's t test). In the group with 120 minutes of MCA occlusion, there was a significant increase in the area of hyperintensity from 24.4±5.2% at 30 minutes of MCA occlusion to 29.1±7.6% at 50 minutes of reperfusion (P<.005, paired Student's t test). At 50 minutes of reperfusion, there was a significant difference between the two groups (P<.005, unpaired Student's t test).

View this table: [in this window] [in a new window]   Table 2. Areas of Signal Hyperintensity in Diffusion-Weighted Images During Middle Cerebral Artery Occlusion and Reperfusion

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Other investigators have used dynamically acquired MR images to study the first passage of a susceptibility contrast agent and have attempted to calculate regional cerebral blood flow and volume by applying tracer kinetic theory to the calculated curves for concentration versus time.^{6 10 11} However, the curve-fitting procedures used in this approach require the assumption of a common pattern for the time series for pixels in the areas of severe and moderate ischemia and nonischemic tissue.⁶ The inaccuracy of this assumption in the case of severe ischemia is clearly illustrated by Fig 3, where there is no clearly defined first-passage peak but rather a gradual buildup of contrast-agent effect. Curve fitting is also problematic in the area with moderate ischemia because the rapid tracer recirculation in rats makes it difficult to distinguish between delayed first passage and recirculation of the tracer. In addition, the calculation of cerebral blood flow also requires certain assumptions about the input function that are dubious in the case of cerebral ischemia.¹³ Hence, it is questionable whether any meaningful results for the mean transit time and cerebral blood flow can be obtained from the perfusion MR images. For these reasons, we chose not to include calculations for cerebral blood flow or mean transit time in this study. Instead, two simple parameters (the maximum signal reduction and time delay to maximum signal reduction) of the curves for signal intensity versus time were estimated. The topographic maps of these two parameters as derived from the perfusion images during MCA occlusion displayed a central area with a small maximum signal reduction and a larger area with an increased time delay. The central area depicted in the signal reduction maps corresponded to the lateral caudoputamen in all rats and in some rats also involved the adjacent lower frontoparietal cortex. In this experiment, the parametric values were not compared with other means of measuring cerebral flow; however, other studies have identified the above-mentioned anatomic areas as the areas of maximal perfusion reduction in Wistar rats with MCA occlusion by the intraluminal filament technique.^{27 28} The time delay maps included both the lateral caudoputamen and the upper frontoparietal cortex in all rats. This latter area has a less severe reduction in perfusion^{27 28 30} and may be rescued by relatively prompt reperfusion,³¹ in accordance with the concept of the ischemic penumbra being the salvageable area of a stroke lesion.³² In our experiment, this area was characterized by near-normal maximum signal reduction and significant increase in the time delay compared with the contralateral hemisphere. We hypothesize that this may reflect perfusion through the collaterals known to exist in the MCA territory of this rat strain.³³ This same pattern was also found in the perifocal penumbra in a recently reported MR imaging case study of a patient with a 3-hour-old stroke.³⁴

During reperfusion, there were no significant differences between the ipsilateral and contralateral hemispheres in the maximum signal reduction maps (Fig 5). There was, however, a slightly increased time delay in the formerly ischemic hemisphere (Fig 6). This delay was significantly smaller than that observed during MCA occlusion and was not due to perfusion through collaterals because the nylon filament was removed from the ipsilateral internal carotid artery. Furthermore, inspection after death with the operating microscope did not reveal any signs of secondary thrombotic occlusion due to the mechanical occlusion. The time delay in reperfusion was the same in both the lateral caudoputamen and the upper frontoparietal cortex and was independent of the duration of the MCA occlusion (Fig 6). It is therefore unlikely that it was related to the severity of the ischemic tissue injury.

In the present study, the hyperintensity in the DW images was observed in the core areas of severe ischemia, thus conforming to the hypothesis that these changes are related to energy failure and intracellular edema^{19 20 21 22} and therefore are only seen in the case of severe ischemia. We also found that the DW hyperintensity in the core was partly reversible with reperfusion after MCA occlusion lasting 45 minutes but not after MCA occlusion lasting 120 minutes. This is in accordance with published histology studies in the same rat model indicating that the critical duration of MCA occlusion for irreversible tissue damage in the core is between 30 and 60 minutes.^{27 31} With a 3-mm-thick MR image slice, each voxel may contain a mixture of ischemic and nonischemic tissue, especially in perifocal areas. This partial volume effect may result in discrepancies between calculated areas from histological sections and DW images, and this may be the reason for the slight, nonsignificant overestimation of the mean area of ischemic injury with DW imaging. The small difference in calculated areas may also reflect the fact that the ischemic injury was not fully developed at the time of histological examination. However, there was a significant correlation between the size of the areas of ischemic injury as measured histologically and as measured in DW images obtained at approximately the same time.

Several rat MCA occlusion studies have reported a gradual extension of the area of DW hyperintensity after permanent MCA occlusion.^{5 16 17 35 36 37} These results may be explained by a time-dependent extension of the area of energy failure into the perifocal penumbra.^{32 38} There are, however, conflicting results concerning DW imaging in perifocal areas also during the first hour after MCA occlusion in rats. We could not demonstrate increased hyperintensity in the upper frontoparietal cortex in this study, except for one rat (Fig 7C). Some investigators have reported hyperintensity also in perifocal regions,^{3 15} while other studies agree with the results reported here.⁵ Possible explanations for these discrepancies may be differences between rat strains or MCA occlusion models or biological variations in the severity of the ischemic insult in the same rat model.³⁷ However, in two rat studies^{17 18} in which an apparent diffusion constant was calculated, perifocal areas with smaller reduction in the translational movement of water were found. We therefore cannot exclude that the lack of calculated apparent diffusion constant values in the present study may explain the insensitivity of the DW imaging to early tissue damage in the penumbra.

We conclude that the perfusion imaging was able to demonstrate a perfusion deficit in the ischemic hemisphere. Relative to the nonischemic hemisphere, the changes in the topographic maps of maximum signal reduction occurred mainly in the lateral caudoputamen, whereas the topographic maps of time delay also included the upper frontoparietal cortex as a region of significant change. The perfusion imaging was also able to demonstrate reperfusion in the former ischemic hemisphere after reversal of MCA occlusion. Hyperintensity in DW images was reversible after 45 minutes but not after 120 minutes of MCA occlusion. This suggests a possible future role for these two imaging methods in acute stroke diagnosis and in the evaluation and follow-up of thrombolytic therapy. The clinical relevance of these techniques needs to be addressed in further studies.

	Acknowledgments

 
This study was supported in part by the Norwegian Council on Cardiovascular Diseases and Nycomed Imaging A/S and by a fellowship from Consiglio Nazionale delle Ricerche, Italy (Mr Sebastiani).

Received April 13, 1994; revision received September 26, 1994; accepted November 10, 1994.

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