Journal of Cerebral Blood Flow and Metabolism 16:60-68 © 1996 The International Society of Cerebral Blood Flow and Metabolism Published by Lippincott-Raven Publishers, Philadelphia

Temporal Correlation Analysis of Penumbral Dynamics in Focal Cerebral Ischemia

E. H. Lo, J. Rogowska, P. Bogorodzki, M. Trocha, K. Matsumoto, B. Saffran, and G. L. Wolf

Center for Imaging and Pharmaceutical Research, Department of Radiology, Massachusetts General Hospital,

Harvard Medical School, Boston, Massachusetts, U.S.A.

Summary: A novel temporal correlation technique was used to map the first-pass transit of iodinated contrast agents through the brain. Transit profiles after bolus in­jections were measured with dynamic computed tomog­raphy (CT) scanning (1 image/s over 50 s). A rabbit model of focal cerebral ischemia (n = 6) was used, and dynamic CT scans were performed at 30, 60, 90, and 120 min post­occlusion. Within the ischemic core, no bolus transit was detectable, demonstrating that complete ischemia was present after arterial occlusion. In the periphery of the ischemic distribution, transit dynamics showed smaller peaks, broadened profiles, and overall delay in bolus transit. A cross-correlation method was used to generate maps of delays in ischemic transit profiles compared with normal transit profiles from the contralateral hemisphere.

The majority of functional imaging techniques, including ultrafast magnetic resonance imaging and computed tomography (CT), are based on dynamic scanning protocols that monitor the first-pass tran­sit of injected boluses of contrast agents through the brain (Axel, 1980; Berninger et aI., 1981; Norman et aI., 1981; Rosen et aI., 1994; Fischman et aI., 1995). Based on traditional Stewart-Hamilton kinetics (Zi­erler, 1962), one can calculate perfusion-dependent

parameters, including relative blood volume and blood flow indexes, from the concentration-time curves of the first-pass transit of injected contrast agents. Although absolute calculations for heteroge­neous tissue may be theoretically difficult to

Received March 14, 1995; final revision received May 15, 1995; accepted May 15, 1995.

Address correspondence and reprint requests to Dr. E. H. Lo at Center for Imaging and Pharmaceutical Research, Harvard Medical School, MGH-East Bldg. 149, 13 St. , Charlestown, MA 02129, U. S.A.

Abbreviations used: CT, computed tomography; TTC, 2,3,5-triphenyltetrazolium chloride.

60

These maps showed that penumbral regions surrounding the ischemic core had significantly delayed bolus transit profiles. Enlargement of the ischemic core over time (from 30 to 120 min postocclusion) was primarily accom­plished by the progressive deterioration of the penumbral regions. These results suggest that (a) temporal correla­tion methods can define regions of abnormal perfusion in focal cerebral ischemia, (b) peripheral regions of focal cerebral ischemia are characterized by delays in bolus transit profiles, and (c) these regions of bolus transit delay deteriorate over time and thus represent a hemodynamic penumbra. Key Words: Cerebral blood flow-Dynamic computed tomography-Functional imaging-Ischemic penumbra.

achieve (Weisskoff et aI., 1993), these approaches can at least provide relative measures of cerebral perfusion.

It has been shown that ultrafast functional imag­ing can be used to map perfusion deficits in cerebral ischemia (Matthews et aI., 1992; Rosen et ai., 1994). In principle, the integrated areas under the first­pass concentration-time curves are proportional to blood volume, and the areas divided by mean tran­

sit times reveal a relative blood flow index (Zierler, 1962; Axel, 1980). However, in addition to discrete reductions in perfusion, more subtle alterations in perfusion dynamics may also occur in cerebral isch­emia. For example, it has been shown that even in areas with apparently normal blood volume and flow indexes, significant alterations in the shape of the bolus transit profile may be present (Roberts et aI., 1993). These include broadening of the bolus profile and delays in peak arrival times. It has been

hypothesized that these temporal changes may rep­resent sluggish flow and/or collateral supply in the face of abnormal perfusion pressures (Roberts et

DYNAMIC IMAGING OF HEMODYNAMIC PENUMBRA 61

aI., 1993). Therefore, it is possible that alterations in bolus transit dynamics may provide a more sensi­

tive marker for ischemic perturbations than gross reductions in blood volume or flow rates per se. Such alterations may be especially important in the ischemic penumbra (Roberts et aI., 1993).

In this report, we describe the use of a novel temporal correlation technique for analyzing the temporal changes in bolus transit dynamics in focal cerebral ischemia. We have previously shown that temporal correlation methods can be used to ana­lyze functional images of the brain (Rogowska et

aI., 1992, 1994, 1995; Rogowska and Wolf, 1992). We test the hypothesis that our method can define ischemic perturbations based on delays in bolus transit times. We aim to show that a "hemodynamic penumbra" is present in the periphery of a focal ischemic insult. This hemodynamic penumbra can be defined as a region where perfusion deficits are moderate but bolus transit times are delayed. Our experiments were designed to map these regions of bolus transit delay, document their evolution over

time, and compare these maps to histological out­comes of ischemic tissue damage.

METHODS AND MATERIALS

Animal model A previously described rabbit model of focal cerebral

ischemia was used (Lo and Steinberg, 1992; Lo et ai., 1993, 1994b). Briefly, ischemia was induced in male New Zealand White rabbits (3-3.5 kg) by electrocoagulation of the middle cerebral artery via a transorbital approach. The internal carotid and anterior cerebral arteries were also coagulated to achieve consistent ischemia. Rabbits were anesthetized with halothane (1-2%) and artificially ventilated with an air/oxygen (5: 1) mixture. Arterial blood pressure, pH, and gases were monitored and maintained within normal limits. Rectal temperature was monitored with a temperature probe and maintained at 37-38°C with a heat lamp.

Dynamic CT Dynamic CT scanning (150 mA, 120 kV) was performed

with a Toshiba TCT-900S/X system (Toshiba Medical Systems, Tokyo, Japan). Based on sagittal scout images and guided by the location of the craniectomy, a single coronal slice was selected to encompass the middle cere­bral artery territory (see Fig. 1). Pixel sizes were 0.15 x 0.15 mm for each 2-mm-thick coronal slice. Dynamic im­ages were collected at a rate of 1 image/so For each study, a baseline of 10 images was obtained followed by a bolus injection of iodinated contrast agent ( 1.2 mllkg Om­nipaque; Sterling-Winthrop) via the femoral vein. A total of 50 images were collected for each dynamic study. Each rabbit was scanned at 30, 60, 90, and 120 min postocclu­sion.

Temporal correlation analysis Dynamic CT data were plotted as signal intensity ver­

sus time curves for each pixel within the brain. CT signal

intensity is measured using standard Hounsfield units. During baseline, the curve is flat. When the bolus of con­trast agent arrives in the brain, signal intensity goes up. When the bolus leaves the brain, signal intensity comes back down again. Each curve therefore represents the first-pass transit profile of the injected contrast agent through that particular pixel in the brain.

After focal ischemia, transit profiles from the ischemic hemisphere are altered either because they have no bolus transit at all (i.e., no flow) or the shape of the transit profile has been changed (Fig. 1). In the center of the ischemic insult where perfusion is almost zero, first-pass transit of the injected contrast agent will be basically eliminated. In peripheral regions surrounding the core, flow is not zero but transit profiles are altered because they are delayed (Fig. 1).

Normal transit profiles are drawn from a reference re­gion within the contralateral cortex (Fig. 1). Delays be­tween ischemic versus normal transit profiles are ob­tained by calculating the delay between peaks in bolus transit from each pixel and that of the contralateral ref­erence profile. The normalized cross-correlation function (CCOR) with the time lag t1t between transit profile S(t) from each pixel versus the reference profile R(t) from the contralateral hemisphere is computed for various time lags ranging from 0 to 6 S. We chose a maximum time lag of 6 s because our pilot data showed that no transit pro­files in ischemic brain had delays of >6 S. The delay between peak arrival time in each pixel and that of the reference profile is defined as the value of the time lag t1t for which the cross-correlation

CCOR(M) =

50

� [S(t) - ILs][R(t + t1t) - ILR] t=i

f 50 50

1 l�[S(t) - ILS]2� [R(t + t1t) - ILRf 112

has a maximum. ILs and ILR are the mean values of S(t) and R(t), respectively.

CCOR will have values ranging from - 1 to 1. To obtain statistical thresholds for the calculated correlation coef­ficients, we assumed that CT noise was normal and de­rived a t statistic for each cross-correlation coefficient. Each dynamic scan generated 50 images (over 50 s) re­sulting in 48 df Seven cross-correlations were used for each delay map to range from 0 (no delay in peak arrival versus reference) to 6 s, each of which could be "signif­icant. " To have an overall chance of ,,;;0.05 of at least one significant cross-correlation (assuming the null hypothe­sis of no correlation at all), we set the p value for each cross-correlation at 1 - ( 1 - 0.05)1/7 = 0.0073. From the t statistics, p < 0.0073 corresponds to a threshold of CCOR of >0.345. Therefore, only cross-correlations of �0.345 are used for the delay calculations.

Based on these pixel-by-pixel calculations, a paramet­ric delay map is constructed. In the ischemic core, where no significant cross-correlations are obtained, pixels are given the value - 1. All other pixels are given values equal to the time of bolus transit delay (in seconds). Since our dynamic CT scans are collected at a rate of 1 image/s, we cannot be certain that regions with bolus delays of 1 s

J Cereb Blood Flow Metab. Vol. 16. No.1. 1996

62 E. H. LO ET AL.

25 20 15 10

R(t)

5 O����--4---�­

- 5

Time (sec)

ca-C I/) CI.t: .- r: I/) ;:)

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ca C I/) CI.t: .- C I/) ;:).

I-0 'tJ C 'ii

:= I/) CI.I C CI :::J C 0 ca:I: "£-

SI(t)

25 20 1 5 10

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Time (sec)

S2(t)

25 20 1 5 10

5 0

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Time (sec)

FIG. 1. A schematic showing the selection of the reference region of interest that is drawn to encompass the cortical areas of the contralateral hemisphere. The reference transit profile R(t) is obtained from this region. Transit profiles in the ischemic side are different from the reference profile because they are either absent (i.e., no bolus transit is detectable) or bolus transit is delayed so that the shape is changed. Two examples are shown in this figure: S1(t), where no bolus transit is detectable, and S2(t) , where bolus transit is delayed. Note that computed tomography (CT) scans are obtained with rabbits in a supine position so that all images are shown with the dorsal surface of the brain on the bottom.

are actually different from regions with no delay at all. To be conservative, we choose our cutoff as twice the sam­pling rate. Hence, ischemic core is defined as regions with no detectable bolus transit profile, and the hemody­namic penumbra is defined as regions surrounding the core with delays of �3 s.

Calculation of perfusion index To obtain a "perfusion index," bolus transit profiles

from various brain regions (core, penumbra, normal) were fitted with "i-variate functions (Hamberg et aI., 1993). The integral (area under curve) of these "i-variate fits was then calculated to assess relative blood volume (Hamberg et aI., 1993). These measurements of relative blood volume were normalized with respect to values from the contralateral hemisphere and used as an index to assess "perfusion" deficits in the various brain regions analyzed (Hamberg et aI., 1993; Roberts et aI., 1993). As explained already, we can only reliably differentiate de­lays of at least twice the sampling rate (l image/s). There-

J Cereb Blood Flow Metab, Vol. 16, No.1, 1996

fore, the various regions of delay are grouped into 2-s intervals. Analysis is performed on core, 1- to 2-,3- to 4-, and 5- to 6-s delay regions.

Histological outcomes After the final CT scan at 120 min postocclusion, rab­

bits were removed from the scanner and maintained un­der halothane anesthesia for an additional 2 h. The rabbits were then killed after 4 h postocclusion to assess the his­tological outcomes of ischemia. The brains were re­moved, cut into 2-mm-thick coronal slices, and stained with 2% 2,3,5-triphenyltetrazolium chloride (TIC). After immersion in TTC for at least 30 min, brains were fixed in formalin. Areas of ischemic damage were defined as re­gions that lacked the typical brick red staining of normal tissue. Since dynamic CT offers only single slice data, a single corresponding histological slice was selected for comparison with the CT analysis. This slice was selected based on a stereotaxic rabbit brain atlas (Girgis and Wang, 1988) to correspond with the CT slices. Lesion

DYNAMIC IMAGING OF HEMODYNAMIC PENUMBRA 63

areas were quantified with computer-based image analy­sis and expressed as the percentage area of the ipsilateral hemisphere.

RESULTS

Systemic parameters were monitored and main­tained during all experiments (Table 1). Delay maps showed that core regions of no-flow were sur­rounded by a hemodynamic penumbra where bolus transit profiles were delayed compared with normal transit profiles from the contralateral hemisphere

(Fig. 2). In all six rabbits, these maps also showed an evolution of the ischemic lesion over time; the penumbra succumbed as the core expanded (Fig. 3).

The cerebral perfusion index in areas that showed no delays in bolus transit profiles remained stable over the course of the experiment. Regions with delays of 1-2 s showed some slight decline but were not significantly different from the regions with no delay at all (Fig. 4). Within the hemodynamic pen­umbra (defined as regions with bolus transit delays of 2:3 s), the perfusion index at 30 min was initially

reduced to 40--70% of contralateral values. From 30 to 120 min postocclusion, perfusion in these pen­

umbral regions continued to decrease, reflecting the deterioration of the penumbra and expansion of the ischemic core (Fig. 4). Overall, core areas with no­flow grew by 34% from 30 to 120 min postocclusion. Regions that were recruited in this evolution pro­cess were composed primarily of areas with high delay values compared with the distribution in nor­mal brain that does not succumb over time (Fig. 5).

After 4 h of focal ischemia, TTC-stained histolog­ical slices showed the typical distribution of isch­emic damage expected with this model, encompass­ing the basal ganglia and frontal and temporal cor­tex. The average TTC lesion area at the slice of CT analysis involved 51 ± 11% of the ipsilateral side. Delay maps at 2 h showed smaller areas of no-flow core (33 ± 12%). This demonstrated that the isch­

emic lesion continued to grow from 2 to 4 h postoc­clusion. However, comparison of the TTC lesion sizes with the delay maps showed a trend whereby ischemic damage was inversely related with mea­surements of the hemodynamic penumbra (Fig. 6).

Rabbits with relatively small penumbral areas and well developed cores at 2 h had the largest TTC

lesions by 4 h postocclusion. Rabbits with relatively larger penumbral areas remaining at 2 h postocclu­sion had the smallest TTC lesions.

DISCUSSION

The penumbra can be defined as the peripheral region that surrounds the core of a focal ischemic insult. The precise distribution of the penumbra de­pends on the specific physiologic or pathophysio­logic process being measured; i.e., there are differ­ent types of "penumbras." The original electro­physiologic penumbra was first defined in the 1970s by Astrup, Symon, and colleagues as a region where spontaneous electrical activity was sup­pressed but ionic homeostasis and membrane po­tentials remained intact (Astrup et al., 1977, 1981). Since then, many other types of penumbra have been defined, including the blood flow penumbra (regions of moderately decreased flow) (Kaplan et al., 1991; Hakim et al., 1992; Tyson et al., 1984), the

metabolic penumbra (regions of increased metabo­lism coupled with decreased flow and increased ox­ygen extraction fraction) (Baron et al., 1989; Mies et al., 1991; Heiss et al., 1994), the gene expression penumbra (regions where certain immediate early genes are selectively expressed) (An et al., 1993;

Kinouchi et al., 1994), the histologic penumbra (re­gions with selective neuronal damage adjacent to fully infarcted areas) (Torvik and Svindland, 1986;

Nedergaard, 1987), and the pharmacologic penum­bra (regions where acute ischemic injury may be

reversed via therapy) (Memezawa et al., 1992; Minematsu et al., 1993; Lo et al., 1994a).

In this report, we defined a new kind of penumbra in focal ischemia: the hemodynamic penumbra. The hemodynamic penumbra is based on changes in the temporal dynamics of blood flow (i.e., hemodynam­

ics) rather than the absolute value of blood flow per se. It was defined using a novel technique devel­

oped in our laboratory. The technique is based on temporal correlation analysis of first-pass transit profiles of injected contrast agents. First-pass tran­sit of contrast boluses through the brain is measured

TABLE 1. Systemic parameters (mean ± SD)

MABP (mm Hg) pH Pco2 (mm Hg) P02 (mm Hg)

Preischemia

67. 1 ± 12 7. 332 ± 0 . 10

32. 3 ± 5 176 ± 43

30 min

56. 8 ± 16 7. 295 ± 0.07

32. 5 ± 6 149 ± 45

Postischemia

60 min

65. 8 ± 12 7.289 ± 0.05

36. 2 ± 8 153 ± 34

90 min

69. 8 ± 12 7. 293 ± 0.05

33. 6 ± 6 209 ± 42

120 min

66. 0 ± 17 7. 328 ± 0 . Q2

30. 2 ± 4 186 ± 38

J Cereb Blood Flow Metab. Vol. 16. No.1. 1996

64 E. H. LO ET AL.

(A)

• 2 3 4 5 -I

(B)

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c no delay :::> 30 "0 1-2 s delay 225 � 3-4 s delay � 20 I 5-6 s delay Iii 15 c 0>

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ischemic core

6 -5�------T_----�------,_------T_----� ° 10 20 30 40 50

Time (sec)

FIG. 2. A: Delay map at 30 min postocclusion shows that the core is surrounded by a hemodynamic penumbra where bolus transit is not eliminated but rather delayed. The delay map corresponds to a coronal section with the dorsal surface of the brain on the bottom (see Fig. 1). The scale shows the range of delay values (0-6 s). Core areas with no-flow are given the value - 1. B: Transit profiles from the same brain. No bolus transit is present in the core (dotted line). Bolus transit in normal brain (solid line) results in a transient increase in computed tomography (CT) signal of �30 HU. The various regions of bolus delay are shown as dashed lines. Bolus transit in these regions is smaller and progressively delayed. For purposes of clarity, regions with delays of 1-2, 3-4, and 5--6 s are grouped together.

with fast CT scanning. In the ischemic core, no flow is present; therefore, no first-pass transit of the in­jected contrast bolus is detectable. Surrounding the core, the hemodynamic penumbra is defined as re­gions where first-pass bolus transit is not eliminated but delayed so that the shape of the bolus transit profile is different from that in normal brain. Our technique produces parametric maps that can be used to quantitatively image these regions. In this study, we demonstrated that (a) peripheral regions of focal ischemia were characterized by delays in bolus transit, (b) these regions of bolus delay dete­riorated into no-flow regions over time (i.e., be­came core), and (c) ratios of no-flow versus delayed transit areas were well correlated with ischemic tis­sue outcomes measured with TTC staining.

The mechanisms that may underlie the delays in bolus transit within the ischemic periphery are pres­

ently unclear. In the ischemic core, the lack of flow is reflected by an absence of bolus transit alto­gether. However, it is possible that, in the face of decreased perfusion pressures, regions in the isch­emic periphery are temporarily sustained via collat­eral supplies. Collateral routes of supply may take a longer time to reach the brain than normal and di­rect arterial routes, thus resulting in delays in bolus transit (Takahashi et aI., 1983; Araki et aI., 1987). Alternatively, these regions may also be subject to sluggish flow due to the regional loss of perfusion

J Cereb Blood Flow Me/ab, Vol. 16, No. I, 1996

pressures (Symon, 1987). It has been shown that one of the first signs of cerebral ischemia is the development of "sluggish flow" as compensatory vasodilation reduces blood velocities (Powers, 1991). Sluggish flow may also be mediated by leu­

kocyte adhesion and/or platelet accumulation pro­cesses (del Zoppo, 1994), although the relatively

early time course of the events documented in the present study may make these factors rather un­likely. Regardless of the actual mechanisms in­volved, we have shown that peripheral regions of ischemia are defined by bolus transit delays. We believe that these regions comprise hemodynami­cally challenged brain that is distinct from no-flow regions in the ischemic core. As such, these areas represent a hemodynamic penumbra in focal cere­

bral ischemia. Relative perfusion deficits in the hemodynamic

penumbra are initially moderate (-40-70% of base­line levels at 30 min). However, these regions de­teriorate over time and are mostly converted into no-flow core areas by 2 h postocclusion. A large literature in different animal models of cerebral ischemia suggests that thresholds for loss of electri­cal activity, Na/K gradients, Ca homeostasis, and cellular ATP may be much lower (15-20%) (Heiss, 1992). It is, however, important to recognize that these thresholds may differ for different time peri­

ods of observation. Hence, more moderate isch-

DYNAMIC IMAGING OF HEMODYNAMIC PENUMBRA 65

o 1 2 3 4 5 6 -1

FIG. 3. A: Map of bolus transit delays at 30 min postocclusion (calculated relative to peak arrival time in reference region of interest). Color scale shows the distribution of delays ranging from 0 to 6 s. Regions with bolus transit delays represent the hemodynamic penumbra that surrounds the ischemic core. The ischemic core with no detectable bolus transit is labeled -1 and colored black. B: Delay map at 60 min postocclusion. C: Delay map at 90 min postocclusion. 0: Delay map at 120 min postoc­clusion. Delay maps show the evolution and spread of the ischemic distribution over time. In this animal, the penumbra also appears to move out as a "wavefront" as damage spreads.

emic deficits over long periods of time may account for similar ischemic injury as more severe ischemia over shorter periods of time (Jones et aI., 1981). A more precise comparison of flow thresholds with our delay maps was not possible since we did not measure absolute blood flow.

There were several limitations to the present study. First, blood flow measurements with tradi­tional techniques (e.g., microspheres, autoradiogra-

phy, etc.) were not performed. However, our pri­mary purpose was not to compare perfusion in­dexes with absolute blood flow numbers, but rather to apply a new method for defining the hemody­

namic penumbra based on bolus transit dynamics. Furthermore, the relative perfusion deficits ob­served in this study matched previous measure­ments in this model using laser Doppler flowmetry and radioactive micro spheres (Lo and Steinberg,

J Cereb Blood Flow Metab, Vol. 16, No.1, 1996

66 E. H. LO ET AL.

OJ § 1 .---�----------------� g -g 0.8 o

:is

.� 0.6 "' � :; 0.4 "0 c � 0.2 o

'iii " � 0�---r---'----'---4---� g.. 0 30 60 90 120 150

Time Post-Occlusion (min)

� nodelay __ 1-2 sec delay __ 3-4 sec delay ___ 5·6 sec delay

FIG. 4. The hemodynamic penumbra deteriorates over time. Relative blood volume (area under curve) is calculated as a cerebral perfusion index. The data show that in the hemody­namic penumbra, perfusion is reduced to 40-70% of contra­lateral values at 30 min postocclusion. Perfusion in these penumbral regions progressively decreases from 30 to 120 min postocclusion as the penumbra deteriorates and ulti­mately becomes core. Perfusion in areas without bolus tran­sit delay does not deteriorate. Mean:±: SO, n = 6.

1991; Steinberg et al., 1991). Second, the final delay maps were obtained at 2 h postischemia, whereas histological tissue damage was assessed at 4 h. This was because 4-6 h postischemia is the earliest time­point before reliable results can be obtained with TTC staining (Kucharczyk et al., 1991; Nishikawa et al., 1993; Roberts et al., 1993). Our results, how­ever, show that the severity of final tissue damage can be predicted by the relative areas of penumbra versus core that remain by 2 h postocclusion. It is also important to note that, even at 4 h, TTC mea­

surements provide assessments of only acute isch­emic injury and not completed infarction per se. This approach has been successfully used by other labs in various models of acute focal ischemia (Ku-

0.8 ..,.,-----------------------------,

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a.

D regions that become core by 120 min

o 2 3 4 5 6 Delay in Bolus Transit (sec) at 30 min post-occlusion

FIG. 5. Quantitative analysis of the process of penumbral de­terioration was performed by defining regions that were not core at 30 min but then proceeded to succumb and become core by 120 min postocclusion. Histogram distributions show that the regions that become converted into core between 30 and 120 min postocclusion are composed primarily of pixels with high delay values (3-6 s) at 30 min postocclusion. In comparison, brain regions that do not deteriorate from 30 to 120 min are composed primarily of regions without signifi­cant bolus transit delays. Mean :±: SO, n = 6; .p < 0.05 for significant differences between the two histogram distribu­tions via analysis of variance with Scheffe's test.

J Cereb Blood Flow Metab, Vol. 16, No. 1, 1996

0.8 ..,.-----------------------,

r=-0.829 p = 0.04

0.2 4---r----r----,--,---,.---,---j o 0.2 0.4 0.6 0.8 1.2 1.4

penumbra/core area ratio FIG. 6. Linear regression analysis of the penumbra/core area ratios at 120 min versus 2,3,5-triphenyltetrazolium chloride (TTC) lesion sizes at 4 h postocclusion. Animals that still have relatively large penumbras at 2 h end up with the smaller lesions. In cases where the cores are well developed and relatively little penumbra is left at 2 h, the TTC lesions tended to be the largest. It is clear that the actual value of the re­gression slope is heavily influenced by a single animal with a small TTC lesion and large penumbra/core area ratio. There­fore, given the relatively limited number of animals used in this study, the relationship between lesion and penumbra size should be conservatively regarded as a trend at this point.

charczyk et al., 1991; Nishikawa et al., 1993; Rob­erts et al., 1993). Third, our method cannot distin­guish between delays in bolus arrival times per se and delays in the time it takes for the bolus to pass through the region of analysis once it gets there (Axel, 1980). The temporal correlation technique can only calculate the overall delay in the peak of

the bolus transit profile, thus including the effects of both delay components. However, this may not be a significant limitation since it is unlikely that one form of transit delay will occur without the other (Nagata and Asano, 1990). Finally, our dynamic CT protocol can only measure perfusion deficits at a single slice. This limitation prevents us from ana­lyzing volumetric ischemic injury.

In summary, we have applied a novel temporal correlation method to define perturbations in bolus

transit dynamics using functional CT imaging. The data support the hypothesis that regions with delays in bolus transit may constitute a hemodynamic pen­umbra in focal cerebral ischemia. The method pro­duces quantitative images that demonstrate the pro­cess of ischemic evolution and may therefore be useful for monitoring and defining areas at risk after cerebral ischemia. Ongoing studies in our labora­tory explore the correlation between these hemody­namic penumbras and areas that can be rescued with therapy, i.e., the pharmacologic penumbra. If a good correspondence exists, this method may

provide the ability to quantitatively visualize the

DYNAMIC IMAGING OF HEMODYNAMIC PENUMBRA 67

penumbra and monitor stroke therapy in vivo.

Since CT remains the first step in the majority of stroke diagnostic algorithms, the method described in this report will be of immediate relevance.

Acknowledgment: The authors thank Drs. K. Batch­elder, S. Gazelle, E. Halpern, B. Hoop, and M. Moskow­itz for many helpful discussions. The technical staff at our center assisted with the CT scanning protocols. This study was funded by grants from the Sterling-Winthrop Pharmaceutical Research Division, the Whitaker Foun­dation, and the National Science Foundation (ECS-9214839).

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