(Stroke. 1997;28:2060-2066.)
© 1997 American Heart Association, Inc.
Articles |
Correlation Between Motor Impairment and Infarct Volume After Permanent and Transient Middle Cerebral Artery Occlusion in the Rat
From Neurosciences Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, United Kingdom.
Correspondence to Dr Derek C. Rogers, Neurosciences Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom. E-mail Derek_C_Rogers{at}sbphrd.com
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Abstract |
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Background and Purpose There have been a number of recent reports describing the relationship between ischemic damage and various behavioral and functional measures, although there have been few studies that have demonstrated a direct correlation between functional impairment and lesion volume. The purpose of the present study was to assess functional outcome by measurement of motor impairment and to determine whether this correlated to a range of infarct volumes induced by varying the duration of focal ischemic insult in the rat.
Methods Male Sprague-Dawley rats were subjected to 0, 30, 60, or 120 minutes or permanent middle cerebral artery (MCA) occlusion by the intraluminal filament technique. Motor impairment was assessed by the accelerating rota-rod and grid-walking tests, and the brains were perfusion-fixed for histological determination of infarct volume and brain swelling 24 hours after MCA occlusion.
Results Marked impairment in performance of both motor tests was recorded in the 60-minute, 120-minute, and the permanent MCA occlusion groups when compared with sham-operated rats. There were significant correlations between regional infarct volume, brain swelling, and all behavioral measurements (all r2>.5, P<.001).
Conclusions The rota-rod and grid-walking tests of motor performance provide quantitative, objective, and reproducible measures of functional impairment of rats following an ischemic insult. These impairments correlate directly with infarct volume and provide information integral to future studies evaluating the effects of potential neuroprotective agents.
Key Words: cerebral ischemia, focal • reperfusion • motor activity • rat
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Introduction |
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Survivors of a stroke manifest abrupt development of a neurological deficit that can range from nausea and headache to blurred vision, vertigo, dizziness, convulsions, and loss of consciousness. There is also a wide range of motor and sensorimotor deficits including tremor, lack of coordination and partial paralysis. In addition, higher cortical dysfunction is also manifested as amnesia, dementia, delirium, and language and speech disturbances that may render the patient severely disabled. The functional impairment of survivors of cerebral ischemia means that in the assessment of potential therapeutic agents, both histological and functional end points are important.
Middle cerebral artery (MCA) occlusion is a widely used experimental model of ischemic stroke.1 Rat models in particular have provided invaluable understanding of the pharmacology and pathophysiology of focal cerebral ischemia.2 3 4 Hitherto, the subtemporal approach with diathermy occlusion5 has emerged as the standard method of permanent proximal MCA occlusion. However, exposure of the MCA by craniectomy can lead to damage from brain retraction and vessel manipulation, as well as temperature loss and desiccation of the exposed brain.3 Moreover, the surgically invasive nature of this technique results in disturbances of the intracra nial environment and does not easily permit reperfusion. In recent years, the intraluminal suture model of MCA occlusion6 has been used increasingly. As the MCA is occluded via a cervical carotid approach, this obviates the requirement for a craniectomy and all the concomitant problems associated with an open skull preparation. The greatest advantage of this model is that reperfusion can be easily instigated, and thus the duration of ischemia can be precisely controlled.2 3 4
Behavioral and functional assessments have been carried out in conjunction with pathological evaluation in permanent7 8 9 10 11 12 and transient13 14 15 16 rat MCA occlusion models. Although these studies all demonstrate significant functional impairments in ischemic groups compared with sham-operated control animals, the degree of impairment is rarely correlated with the size of infarct. A number of studies using permanent MCA occlusion models have reported significant correlation between specific types of ischemic damage and individual motor deficits,7 17 18 19 although there is little consensus among these reports on the best types of functional analysis to use. Some studies have previously demonstrated correlation between infarct volume and neurological score after transient and permanent focal cerebral ischemia in the rat.14 20 21 22 23 In the present study we have extended the behavioral assessment of ischemic animals to include rota-rod24 25 and grid-walking8 26 tests of motor performance deficits.
The purpose of the present study was to assess functional outcome by measurement of motor impairment and to determine whether functional outcome correlated to the volume of infarction induced by varying the duration of ischemic insult. Our results demonstrate a linear relationship between duration of ischemia and deficits in motor performance recorded 24 hours after the onset of ischemia. Our results suggest that in this model reliable functional data can be produced that can provide additional information for evaluation of potential neuroprotective agents.
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Materials and Methods |
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Surgical Preparation
All procedures used in this study were carried out in accordance with the UK Animals (Scientific Procedures) Act (1986), and were approved by a SmithKline Beecham internal ethics committee. Adult male Sprague-Dawley rats (Charles River, UK, 300 to 350 g) were housed in groups of 4 to 6 and maintained under a natural 12 hour light/dark cycle with food and water available ad libitum. Fifty-seven animals were anesthetized with halothane in nitrous oxide/oxygen (70:30). Anesthesia was induced with 4% halothane and subsequently maintained with 1% to 2% halothane delivered by a face mask. Body temperature was monitored throughout the surgical procedures for MCA occlusion (<30 minutes) and reperfusion institution (<10 minutes) by a rectal thermometer, and the animals were maintained normothermic (37±0.5°C) via a heating blanket controlled by the thermometer.
The left MCA was occluded using the intraluminal suture technique described in detail elsewhere.6 Briefly, the common carotid, external carotid, and internal carotid arteries were exposed through a midline cervical incision. A 30-mm length of 3-0 monofilament nylon suture, its tip heat-blunted to a diameter of 0.26 to 0.30 mm and coated with poly-l-lysine,14 was advanced from the external carotid artery into the lumen of the internal carotid artery until mild resistance was felt (18 to 20 mm), thereby occluding the origin of the MCA. Sham-operated animals (n=10; group A) underwent the same operative procedure but had no suture inserted into the internal carotid artery. In the transient MCA occlusion groups, rats were re-anesthetized with halothane at 30 minutes (n=11; group B), 60 minutes (n=11; group C), and 120 minutes (n=12; group D) after occlusion of the MCA, and the suture was withdrawn completely to institute reperfusion. In the permanent MCA occlusion group (n=13; group E), the nylon filament remained in place until the animals were killed. After surgery, the rats were allowed to recover in an incubator and housed in individual cages with their diet supplemented with soft mash. All animals were weighed before ischemia and perfusion fixation.
Neurological evaluations were carried out after 30 minutes to verify successful MCA occlusion and immediately before they were killed at 24 hours using an eight-point behavioral rating scale, modified from the scale described previously20 : 0=no neurological deficit; 1=failure to extend right forepaw fully; 2=decreased grip of the right forelimb while tail gently pulled; 3=spontaneous movement in all directions, contralateral circling only if pulled by the tail; 4=circling or walking to the right; 5=walks only when stimulated; 6=unresponsive to stimulation with a depressed level of consciousness; and 7=dead.
Motor Performance Tests
Rota-Rod
On the day of and before MCA occlusion, rats were conditioned to
the accelerating rota-rod (Ugo Basile). Each animal received a training
session on the rota-rod set at a constant speed of 8 rpm and were
tested until they achieved a criterion of remaining on the rotating
spindle for 60 seconds. Each rat then received a single baseline trial
on the accelerating rota-rod in which the spindle increased in speed
from 4 to 40 rpm over a period of 5 minutes. At 24 hours postocclusion
each rat received a test trial on the accelerating rota-rod before it
was killed, with the scoring carried out blind to condition.
Grid Walking
Before MCA occlusion, each rat was acclimatized for 1 minute to
an elevated, level, stainless steel grid with a mesh size of 30
mm. At 24 hours postocclusion, the rats were placed on the grid for 1
minute, and the total number of paired steps (placement of both
forelimbs) was counted, with the scoring carried out blind to
condition. During this period, the number of foot-fault errors in which
the animals misplaced a forelimb such that it fell through the grid was
monitored, and the total number of errors for each forelimb was
recorded.
Neuropathology and Quantification of Ischemic Damage
Twenty-four hours after MCA occlusion, all rats were weighed,
terminally anesthetized, and transcardially perfused with
neutral buffered formalin containing 5% sucrose. The brains were
removed, postfixed for 48 hours, and processed for
histological quantification of ischemic
damage.27 Brains were sectioned serially (1.5-mm
intervals) throughout each forebrain, and the sections (50 µm)
stained with 1% cresyl fast violet (Sigma). Those sections that
corresponded most closely to 8 stereotactically
predetermined coronal planes, from anterior +3.0 mm to posterior
-7.5 mm relative to bregma, were examined. Areas of brain with
reduced cresyl fast violet staining, and containing pyknotic-necrotic
neurones, were transcribed onto digitized line diagrams of normal
forebrain at the 8 coronal planes to remove the influence of brain
swelling. The areas of ischemic damage in the cerebral
hemisphere, cerebral cortex, and striatum were determined from the
diagrams, at each of the 8 coronal planes, using an Optimas image
analysis system (DataCell). The volumes of ischemic
damage were calculated by integration from the areas of damage at the
different coronal planes and their anteroposterior
coordinates.27 The degree of associated brain swelling was
determined as the percentage difference in brain volume between the two
hemispheres.
Statistical Analysis
Comparisons of infarct volumes, brain swelling, and motor
performance were carried out by ANOVA, followed by Tukey's
individual comparisons of the means using SAS-RSA (Research Scientists
Application, SAS Software Ltd). Neurological scores were compared by
Kruskal-Wallis analysis followed by the Mann-Whitney
U test to compare medians. Correlation analyses used
Pearson's linear regression, and in all analyses a value of
P<.05 was considered significant.
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Results |
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All ischemic animals exhibited focal neurological deficits 30 minutes after MCA occlusion, with failure to fully extend the right forepaw and circling to the right (neurological score=4). No right-sided neurological deficits (neurological score=0) were observed in sham-operated control animals. Four rats died prematurely within the 24-hour survival period (n=3, group D; n=1, group E). Autopsy revealed large ipsilateral hemispheric infarcts and extensive brain swelling. Another five rats (n=1, group B; n=2, group C; n=2, group E) had evidence of intracranial hemorrhage on brain removal. All 9 rats were excluded from further analysis.
Occlusion of the left MCA for 60 minutes, 120 minutes, or 24 hours
resulted in ischemic damage only within the territory of the
occluded MCA, ie, dorsolateral cortex (motor and sensorimotor
frontoparietal cortex) and lateral and medial segments of the striatum
24 hours after MCA occlusion. Histological
analysis showed that the areas of infarction were well
demarcated and included pancellular necrosis. Thirty-minute occlusion
produced shrunken, pyknotic neurones in the medial segment of the
striatum only with no obvious cortical damage. The volume of infarction
increased with the duration of ischemia to a maximum of
237±7.9 mm3 in the permanent occlusion group. There
was no evidence of ischemic damage in any brains from the sham
group. There was a highly significant difference between the cerebral
hemispheric infarct volumes of treatment groups (F4,
42=133.9, P<.001). Individual comparisons indicated
that there was no significant difference between the permanent and
120-minute occlusion groups or between the the sham and 30-minute
occlusion groups. There were significant differences between all other
treatment groups, P<.05 (Fig 1
, top panel). Separate analysis
of the volume of infarction in the cortex and striatum revealed an
increase in infarction volume with duration of ischemia and
maximum ischemic damage of 126.3±6.3 and 54.4±2.5
mm3, respectively, was observed in the permanent occlusion
group. There were highly significant differences between both the
cortical and striatal infarct volumes of the treatment groups (F4,
42=100.7 and F4, 42=63.9, respectively, both
P<.001). Individual comparisons indicated that there was no
significant difference in cortical or striatal infarct volume between
the permanent and 120-minute occlusion groups, or between cortical
volumes of the sham and 30-minute occlusion groups. There were
significant differences between all other treatment groups,
P<.05 (Fig 1, top panel).
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There was an increase in hemispheric swelling with duration of
ischemia, up to a maximum of 33.9±1.7% recorded in the
permanent occlusion group. There was a highly significant difference
between volume of brain swelling of treatment groups (F4,
42=75.0, P<.001). Individual comparisons indicated
that there was no significant difference between the sham and 30-minute
occlusion groups. There were significant differences between all other
treatment groups, P<.05 (Fig 1
, bottom panel). There was a
significant correlation between the volume of cerebral hemispheric
infarction and the volume of brain swelling
(r2=.56, P<.001).
Before surgery, there was no significant difference between the body
weight of treatment groups (F4, 43=0.32,
P=.86). Loss in body weight over 24 hours increased with
duration of ischemia (Table 1).
There was a highly significant effect of treatment on decrease in body
weight (F4, 42=15.80, P<.001). Individual
comparisons indicated that there were significant differences between
the sham-operated group and all other groups except the 30-minute
occlusion group and that the 60-minute occlusion group was
significantly different from both the sham and the permanent occlusion
groups, P<.05 (Table 1).
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There was a highly significant difference between neurological scores
of treatment groups when assessed at 24 hours (F4,
42=139.1, P<.001). Individual comparisons indicated
that the treatments fell into two groups, where the sham (A) and
30-minute occlusion (B) groups had a median score of 0, and 60-minute
(C), 120-minute (D), and permanent (E) occlusion groups had a median
score of 4 (Table 1).
Before surgery, there was no significant difference between the
treatment groups on the time spent on the accelerating rota-rod
(F4, 43=1.42, P=.24). In contrast, at 24 hours,
rota-rod performance decreased with duration of
ischemia, where the sham group remained on the spindle for a
mean of 114.3±9.2 seconds and the permanent occlusion group for a mean
of 23.3±4.7 seconds (Fig 2). There was a
highly significant effect of treatment on rota-rod performance
(F4, 42=18.84, P<.001). Individual comparisons
indicated that there were significant differences between the sham
group and all other groups except the 30-minute occlusion group, and
between permanent and 30-minute occlusion groups, P<.05
(Fig 2).
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There was a highly significant effect of treatment on grid-walking
activity recorded as total number of steps (F4,
42=6.20, P<.001). Individual comparisons indicated
that there were significant differences between the sham-operated group
and all other groups except the 30-min occlusion group,
P<.05 (Fig 3, top panel).
There was also a highly significant effect of treatment on right
forepaw errors during the grid-walking test recorded as a
percentage of the total number of steps during 1 minute (F4,
42=17.31, P<.001). The sham-operated animals made no
errors in placing the right forepaw on the grid during the test,
whereas the 120-minute and permanent occlusion groups made errors on
more than 60% of forepaw placements. Individual comparisons indicated
that there were significant differences between the sham-operated group
and all other groups except the 30-minute occlusion group and that the
permanent occlusion group was significantly different from the sham,
30-minute, and 60-minute occlusion groups, P<.05 (Fig 3, bottom panel).
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There were significant correlations between all infarct volumes (total,
cortical, or striatal) and all functional measures (motor function,
neurological deficit, and body weight) 24 hours after MCA occlusion
(all r2>.5, P<.001; Table 2). In addition, there were significant
correlations between hemispheric swelling and all functional measures
(all r2>.5, P<.001; Table 2).
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Discussion |
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The requirement to assess functional, as well as histological, outcome in the preclinical evaluation of anti-ischemic agents in experimental models of cerebral ischemia is increasingly recognized. In the present study, the duration of ischemia has been adjusted to produce varying degrees of ischemic insult, and the histological data have been correlated with three tests of sensorimotor function. The results of the present study demonstrate that there are significant correlations between histopathological outcome (infarct volume and brain swelling) and motor function 24 hours after MCA occlusion in the rat.
Postischemic loss in body weight increased with duration of ischemia, and was significantly correlated to both infarction and brain swelling at 24 hours. Sham-operated animals underwent identical surgery, with the exception of intraluminal filament insertion and occlusion of the MCA. Therefore, the body weight decreases are probably due to infarction and brain swelling affecting feeding behavior, and it has been suggested that this may be a consequence of appetite loss secondary to injury to the anterior hypothalamus.28 Thus, body weight appears to be an indirect index of ischemic brain damage. This is illustrated in recent studies where the neuroprotective efficacy of anti-ischemic agents is accompanied by significant attenuations in body weight loss.29 30
In the grid-walking test, rats place their paws on the wire mesh while moving about an elevated grid and occasionally a foot will be misplaced and fall through a grid opening, a foot-fault error. Foot faults are typically near zero in intact animals. Measurement of the total number of steps taken over 60 seconds provided a gross index of spontaneous locomotor activity, and there were significant decreases in the number of steps taken by the rats from the 60-minute, 120-minute, and permanent MCA occlusion groups compared with sham-operated control animals, although this decrease did not alter with severity of insult. In contrast, there was a linear relationship between duration of ischemia (and resultant infarct volume) and number of foot-fault errors up to a maximum of 67% error with the right forelimb in the 120-minute ischemia group. This deficit was completely lateralized in that only two left forelimb placement errors were recorded during the whole study. These findings are consistent with a previous observation, which demonstrated impaired motor coordination in the grid-walking test after permanent occlusion of the MCA.8
It is not possible from the present data to dissociate the relative contribution of infarct volume and edema from the functional effects reported here. It has been demonstrated previously that there is a relationship between brain edema and motor deficits in focal ischemia.7 However, in the same study, it was also reported that the decline in motor impairment after 3 days was less marked than the decrease in edema. Further comprehensive time-course studies are necessary to resolve this issue.
The rota-rod test is a well-established procedure for testing balance and coordination aspects of motor performance in rats and mice.24 Recent evidence has indicated that the accelerating rota-rod task is a more sensitive index for the assessment of motor impairment induced by traumatic brain injury in the rat than both the beam-walking and beam-balancing tasks.25 Deficits in motor performance on the rota rod task have been observed from 24 hours to 2 months after the induction of focal cerebral ischemia in the rat.10 12 15 31 In the present study we have confirmed and extended these observations and demonstrated a linear relationship between the duration of ischemia and the ability of the animals to remain on the accelerating rota-rod at 24 hours post-MCA occlusion; increasing infarct volume was significantly correlated with impaired rota-rod performance.
Previous studies have assessed functional outcome after MCA occlusion in the rat by the incorporation of a relatively simple measurement of neurological deficit. After ischemia, rats are assigned an arbitrary score on a neurological evaluation scale.12 14 20 21 22 23 32 The neurological grading system subjectively quantifies both reflex and sensorimotor functions.12 22 23 32 In the present study, we have demonstrated that total, cortical, and striatal infarct volumes are correlated with neurological score at 24 hours post-MCA occlusion. This is in agreement with previous observations, where neurological grades have been shown to correlate with area or volume of hemispheric infarction from 24 hours up to 42 days after the induction of ischemia,14 20 21 22 23 although a lack of correlation between infarction and neurological score has been reported.33 The utility of the neurological scoring system as a corollary of neuroprotection in rat models of focal ischemia is best highlighted in drug studies where reductions in ischemic damage have been associated with improved neurological outcome.14 20 21 It is noteworthy, however, that improved neurological outcome has also been observed without a reduction in infarct volume after MCA occlusion in the rat.34
A more complex objective assessment of the functional deficit after MCA occlusion in the rat has been recently described using the staircase task developed by Montoya et al.35 This task provides a measurement of skilled paw use, where independent forelimb reaching and grasping abilities can be quantitatively assessed in rats. Recent evidence has demonstrated a marked impairment in skilled paw use after focal ischemia.9 17 36 This performance deficit is not only significantly correlated to infarct size after MCA occlusion17 but is reduced after anti-ischemic drug administration.36 Although the staircase test is a more complex index of motor function (the rat is required to exert precise motor control over each paw in order to grasp and retrieve reward pellets), there is a need for extensive training over a number of sessions before MCA occlusion and for a recovery time of several days postischemia before functional assessment can be carried out. In contrast, the rota-rod and grid-walking tasks of motor function are relatively rapid, simple, and objective, and, importantly, require minimal pretraining before the onset of ischemia. Thus, these tests of motor performance are suitable for incorporation into neuroprotection studies to provide an important profile of motor function that will supplement standard histopathological analysis at 24 hours postischemia.
A number of factors need to be taken into account to optimize the value of the information that can be obtained from functional studies. One important variable is the postischemic assessment time. Spontaneous recovery of some motor deficits does occur, although impairment of tasks such as paw reaching, for example, is present for up to 3 months after the ischemic insult.17 The comparative effects of a drug on behaviors with a different rate of recovery may be important as well as the effects of different doses of the drug on different behavioral measures. Therefore, selection of the correct functional test battery is essential, and assessment of functional deficits in drug studies requires a clear understanding of the relationship between histopathological damage and functional consequences. Further studies with extended survival periods are necessary to determine the predictive validity of these procedures.
In conclusion, the present study has demonstrated that volumes of infarction in the cerebral hemisphere, cerebral cortex, and striatum, and brain swelling are highly correlated with functional deficits assessed using rota-rod, grid-walking, and neurological score 24 hours after MCA occlusion in the rat. These data suggest that appropriate tests of motor function can provide important information to complement histological data in the assessment of novel neuroprotectants after focal cerebral ischemia in the rat. This, in turn, may provide additional evidence that the effects of neuroprotective agents in preclinical models may have therapeutic functional relevance in the clinic.
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Acknowledgments |
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The authors thank Penelope D. King and Sarah J. Hadingham for expert assistance.
Received May 6, 1997; revision received June 9, 1997; accepted June 25, 1997.
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