Abstract
About 50% of humans with aneurysmal subarachnoid hemorrhage (SAH) die and many survivors have neurological and neurobehavioral dysfunction. Animal studies usually focused on cerebral vasospasm and sometimes neuronal injury. The difference in endpoints may contribute to lack of translation of treatments effective in animals to humans. We reviewed prior animal studies of SAH to determine what neurological and neurobehavioral endpoints had been used, whether they differentiated between appropriate controls and animals with SAH, whether treatment effects were reported and whether they correlated with vasospasm. Only a few studies in rats examined learning and memory. It is concluded that more studies are needed to fully characterize neurobehavioral performance in animals with SAH and assess effects of treatment.
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Introduction
Mortality and morbidity from aneurysmal subarachnoid hemorrhage (SAH) have decreased with improvements in surgery, pharmacological treatment and intensive care. The overall outcome, however, remains relatively poor [1, 2]. Management of SAH includes early obliteration of the ruptured aneurysm to prevent rebleeding, prevention of secondary brain injury from such things as decreased cerebral perfusion and prevention and treatment of delayed neurological deterioration secondary to cerebral vasospasm. The case fatality rate is approximately 50% and 30% of survivors remain dependent on others, mainly due to the persistent cognitive impairment rather than focal neurological deficits [3].
Although the mechanisms underlying the cognitive deficits have not been well studied, they have nevertheless been attributed to ischemic brain injury occurring either during the initial hemorrhage or as a consequence of macro- and microvascular dysfunction and delayed ischemic neurological deterioration (Figure 1) [1]. Other mechanisms, including delayed neuronal death and cortical spreading depression have been suggested [4, 5]. These processes may lead to large-artery territory infarction, smaller cortical laminar infarcts or possibly other types of selective neuronal death or perhaps even dysfunction in the absence of detectable death [6].
The pathophysiology of brain injury after SAH may originate from 3 phenomena; transient global ischemia (due to increased intracranial pressure and decreased cerebral perfusion pressure), subarachnoid blood clot and acute hypertension. These may lead to a variety of secondary effects including brain edema, delayed large artery vasospasm, breakdown of the BBB, microcirculatory changes, thromboemboli, cortical spreading depression and delayed neuronal death due to apoptosis or other mechanisms. The end result is focal and scattered brain injury. The role of astrocytes is increasingly being recognized also. In the end, these processes have to cause neurological and neurobehavior deficits to be important and these will depend on what areas of the brain or networks in the brain are disrupted.
Much work on SAH has focused on cerebral vasospasm. This is based on the assumption that severe vasospasm can reduce cerebral blood flow, cause brain ischemia and infarction and contribute to poor outcome [7]. For such studies, an acceptable dependent variable would be angiographic arterial diameter. This might not detect treatment toxicity, however. Considering the fact that the other proposed mechanisms do not necessarily cause focal cerebral infarctions, how to assess outcome is a problem. Clinically, neurobehavioral testing could be used and generally is done 3 to 6 months post-SAH.
Animal studies have often relied on histological assessment of neuron death but there are several problems with this. The time course of changes needs to be considered since complications of SAH are often delayed for several days. Not much is known about the time course of neuronal injury after SAH but it is notable that neuron death seems to progress over months after experimental ischemic stroke [8]. Furthermore, lack of neuron death associated with a treatment does not necessarily indicate that the rescued neurons are functional. Studies show ischemia treated with ischemic preconditioning or hypothermia prevents neuron death but that behavior is not improved and/or there is an inability to induce long term potentiation in hippocampal slices [8, 9]. Therefore, it seems warranted to employ neurobehavioral testing in models of SAH.
In this paper, we hypothesize that SAH models in animals should cause neurological and neurobehavioral alterations that do not occur in sham-operated animals. Treatments that improve histological or other measures of brain injury should also improve the neurological/neurobehavioral alterations. To this end, literature studying neurological and neurobehavioral alterations after experimental SAH is reviewed to determine what has been done, whether tests used thus far differentiated between appropriate controls and animals with SAH, whether treatment effects were reported and whether neurobehavioral tests correlated with vasospasm. Prior review of animal models focused on vasospasm and didn't mention these endpoints [10]. This review is not exhaustive and we apologize for any omissions. The purpose is not to review the pathophysiology of brain injury after SAH, although when relevant, some discussion of this is provided.
Rats
Models
The most common methods of inducing SAH in rats are to inject blood into the cisterna magna once (single injection) or twice (separated by 1 or 2 days, double injection) or to perforate an anterior circulation intracranial artery endovascularly (perforation model)[10]. Prunell, et al., developed an anterior circulation single injection model where blood was injected into the chiasmatic cistern [11].
Endpoints Used
Mortality
Mortality tends to be lowest with the single injection, is higher with the double-injection and highest with the endovascular perforation model (Table 1) [12–15, 15–23]. Mortality is probably lower if sham surgery is done with injection of artificial cerebrospinal fluid (CSF) or physiological saline but this has seldom been documented. Intracranial pressure also is not usually measured so it is difficult to differentiate effects of subarachnoid blood from those of increased intracranial pressure. The larger the injection volume, the higher the mortality. High mortality rates can be problematic because this may remove animals that have neurologic deficits, leaving only relatively normal animals for assessment.
Body Weight
Body weight reflects in part feeding and drinking behaviour and can be used to assess appetite and motivation. Body weight decreases significantly after SAH created by cisternal blood injection in rats but tends to return to normal within 3 to 5 days [1, 12, 13, 24, 25]. Injecting 300:l blood is associated with less change in body weight than after injecting 400:l. Injection times also were different (15 seconds for 300:l and 30 seconds for 400:l). The injection time affects how high the intracranial pressure rises during the injection and could also affect body weight and neurologic function by causing additional injury beyond that due to SAH itself. Indeed, injection of saline into the cisterna magna of rats also can be associated with weight loss [13].
General Neurological Function
Germano and colleagues provided perhaps the first more detailed neurological evaluation of rats undergoing injection of artificial CSF, autologous blood or nothing into the cisterna magna [13]. This comprised simple nonpostural somatomotor functions (duration of suppression of the pinna reflex, corneal reflexes, startle response) and acute complex postural somatomotor functions (righting response, spontaneous locomotion, escape response) that were summarized from tests developed by other investigators. Detailed quantification was not done and there were no differences between rats undergoing sham-operation or SAH created by cisternal blood injection.
Zausinger, et al., modified a scale developed for assessing neurological function after asphyxia cardiac arrest in rats (Table 2)[19, 26]. The scale was adapted from one developed to study cardiac arrest in dogs [27]. Animals with endovascular SAH had impaired scores by 7 days after SAH in 3 studies but there was no comparison to sham-operated controsls so whether the score detects effects of SAH was not determined [19, 28, 29]. A variation of this scale with 175 points did compare sham operated to rats undergoing endovascular SAH [21]. Significant differences were noted between the sham and SAH groups 6 and 24 but not 72 hours after SAH.
Park, et al., modified a scale that was developed to assess neurological function after focal cerebral ischemia in rats (Table 3) [18, 30]. Animals were rated on spontaneous movement, symmetry of limb movements, forepaw outstretching, climbing, body proprioception and response to vibrissae touch for a score of 3 to 18 points [20, 22, 31]. This scale or modifications of it have repeatedly differentiated rats with endovascular SAH from sham-operated controls 6 to 72 hours after SAH [18, 20, 22, 23, 31–33]. Other scales developed to measure lateralized deficits after middle cerebral artery occlusion in rats were not shown tested in SAH and sham-operated rats (Table 4) [28, 29, 34]. The prehensile traction test also was measured in rats with endovascular perforation SAH but without sham-operated animals [28, 29, 35]. Rats were suspended by their front limbs from a metal rod and the time until falling was measured and treated categorically.
Another 16-point scale developed for rats with traumatic brain injury was studied in rats undergoing SAH by endovascular perforation (Table 5)[36, 37]. The score combines mobility, neurological reflexes, neurobehavior and beam walking. The neurobehavioral test was seeking behavior. Means for shams were not presented but SAH animals had a score that would probably be significantly different from the normal score of 0 to 1.
Silasi and Colbourne did not detect differences in general activity and forelimb asymmetry in rats undergoing sham or endovascular perforation SAH for up to 21 days after SAH [38]. General activity was decreased to a similar degree after SAH or sham-surgery.
Rotarod, Horizontal Ladder and Other Neurological Tests
The rotarod test measures motor function. There are variations in how it is conducted that makes comparison between studies difficult. Thal, et al., placed rats on the device for 10 seconds [29]. Rotation then started and accelerated to 40 revolutions per minute (rpm) within 90 seconds and then remained constant for 30 more seconds. The trial was repeated 5 minutes later and the trial was stopped if the animal fell off or gripped the rungs and spun for 2 revolutions. No sham animals were included. Another method was performed in the double hemorrhage rat model [39]. The rotation was increased from 4 to 40 rpm over 5 minutes for 3 trials per day for 28 days after SAH, sham surgery or saline injection. SAH was associated with marked, persistent deficits for 28 days.
Silasi and Colbourne did not detect differences in tapered beam walking or horizontal ladder function in rats undergoing sham or endovascular perforation SAH for up to 21 days after SAH [38].
Beam Balance Test
The beam balance test assesses motor and vestibular function by quantifying the ability to balance on a narrow wooden beam (diameter of 1–2.5 cm) for up to 60 seconds [1, 13, 14, 25, 29, 40]. Parameters are beam balance time (duration the animal steadily remains on the beam) and beam balance score [13]. Beam balance score is descriptive and examiner-dependent [29].
Rats with single hemorrhage SAH exhibited significantly increased beam balance score 1 day after SAH compared to their function before SAH and to sham-operated and artificial CSF-injected animals [13]. In later studies, the beam balance test was carried out on a wooden beam with a diameter of 1 cm which may increase the sensitivity compared to the 1.5 cm diameter [13].
Most studies using the beam balance were done by one laboratory and although the creation of SAH and behavioral assessments were the same, the results varied, suggesting that the sensitivity is relatively low (Table 1). Deficits usually were detected only in the first 1 to 2 days after SAH [14, 24, 25]. Variable results may be due to several factors including that the score is subjective and descriptive [13]. The severity of SAH caused by cisternal blood injection also is variable [16]. Finally, the beam balance test is not standardized and there is variability in the diameter, length, shape and composition of the beam which may affect the results [29]. Nevertheless, the results consistently show deficits in the first 24 hours after SAH that tend to resolve after that.
Beam Walking Test
The beam walking test is a learned avoidance test. A pre-training session is preceded by a negative reinforcement paradigm in which termination of the adverse stimuli (noise and light) serves as a reinforcement reward. The time taken to traverse the beam and enter a darkened goal box in order to terminate the loud white noise and bright light is measured to assess memory, motivation, attention, somatomotor and locomotor function [13].
Most [1, 13, 25, 40] but not all [14] studies document that rats with SAH created by cisterna magna blood injection take a significantly longer time to traverse the beam compared to before SAH and to sham-operated controls for up to 4 days after SAH. In general, the deficit was maximal 1 day after SAH and then gradually improved. All studies were from one laboratory. Since memory, motivation and attention are involved, this test should be more sensitive to brain injury associated with SAH and this does seem to be the case compared to the other tests described above that assess mainly motor functions.
Morris Water Maze
Numerous aspects of learning, memory and neurobehavior can be tested in this apparatus [41]. There are 2 studies employing it after experimental SAH (Table 1)[38, 39]. Takata, et al., studied rats undergoing 2 injections of blood or saline into the cisterna magna [39]. Mortality was not reported but would be expected to be high based on prior studies and the massive amount of blood that was injected. Rats were tested for escape latency, swimming speed and swim distance for 16, 60-second trials 29 to 35 days after SAH. The platform was placed in a different quadrant each day and rats were placed randomly in 1 of 4 locations in the maze. If the platform was not found, the rat was placed on the platform for 30 seconds in the first trial or 15 seconds in subsequent trials [42]. The procedure tests learning and short-term memory. SAH was associated with significantly longer escape latency, swim distance and faster swimming speed. Morris water maze testing correlated with neuronal counts in the hippocampus and neocortex.
Silasi and Colbourne compared rats with endovascular perforation SAH to sham-operated animals [38]. They were tested in the Morris water maze from approximately day 21 to 40 after SAH. The procedure was similar to that of Takata, et al., but with 4 trials of 90 seconds per day. SAH rats had longer escape latency and swim distance on days the platform was moved to a new location (every second day). There were Fluoro Jade stained neurons in 4 of 5 SAH rats examined but no other histopathological changes.
Does Treatment of SAH Affect Neurological Tests?
The only treatments that have reduced mortality in rats undergoing endovascular SAH are hyperbaric oxygen [32] and pifithrin ∀ (Table 1)[20, 31]. These studies provide some insight into the complex pathophysiology of brain injury after SAH (Figure 1). These authors hypothesized that hypoxic brain injury at the time of SAH induced apoptosis in large artery endothelial cells by activation of hypoxia-inducible factor 1∀ (HIF1∀). Hyperbaric oxygen decrease expression of HIF1∀ and its target genes, BNIP3 and vascular endothelial growth factor. This was associated with less neuronal injury, improved cerebral blood flow and improved behavior 24 hours after SAH [32]. Apoptosis was inhibited with pifithrin ∀, resulting in less vasospasm and improved blood-brain barrier (BBB) integrity and neurological function [20, 31].
Weight loss was assessed in 2 studies. The oxygen free radical scavenger +/- N,N' -propylenedinicotinamide (AVS) did not affect weight loss in rats undergoing single hemorrhage SAH [40]. AVS did improve other endpoints such as vasospasm, balance beam and beam walking, which suggests a role for free radicals in vasospasm and brain injury after SAH and is in keeping with clinical studies showing beneficial effects of AVS [43]. The calpain inhibitor, N-acetyl-leu-leu-methioninal and felbamate prevented body weight reduction for up to 5 days after SAH in the same model [1, 25]. Calpains are calcium-activated neutral proteases that may be activated in cerebral blood vessels after SAH, leading to vasospasm and breakdown of the BBB [25]. Thus, preventing their activation may preserve the BBB, as shown by Germano and colleagues [25]. Felbamate has multiple actions that may be neuroprotective including inhibition of voltage-dependent sodium and calcium channels, potentiation of (-amino-butyric acid-mediated chloride currents and reduction of excitatory glutaminergic neurotransmission via N-methyl-D-aspartate receptors [1].
A number of studies demonstrated what would be expected to be beneficial effects on the brain such as neuronal preservation, less vasospasm, less BBB breakdown and/or less brain edema yet found only minimal effects on behavioral testing, suggesting that general neurological scales were not very sensitive to alteration by treatment. The 100 point neurological evaluation or variations of this were different only 1 day after endovascular SAH when treating with hypertonic saline [19] or hypertonic saline plus dextran 70 [29]. Another study comparing infusions of NaCl, mannitol, dextran and hydroxyethylstarch found no differences between groups for up to 7 days after SAH [28]. In all 3 studies, there was less neuronal loss in some of the treated groups at 7 days.
The scale modified from Garcia, et al., differentiated rats 24 hours after endovascular SAH and treatment with caspase inhibitors, hyperbaric oxygen, pifithrin ∀, simvastatin and tetramethylpyrazine [18, 20, 22, 23, 32, 33]. All treatments improved multiple measures of brain injury. Significant differences persisted for 72 hours among rats treated with pifithrin ∀ compared to dimethylsulfoxide (DMSO) after endovascular SAH [31]. Deficits measured on the scale of Bederson, et al., impairment on the prehensile traction test and rotarod testing, all of which would tend to assess focal motor deficits, were only minimally or not impaired after endovascular SAH or did not differentiate treatment effects [28, 29].
The 16-point scale developed for traumatic brain injury [36] detected improved scores in rats undergoing endovascular SAH and treatment with the kinase inhibitor SP600125 compared to DMSO [37]. This scale has advantages of including measures of motor and sensory function as well as beam walking and mobility that may assess higher neurological functions more likely to be impaired after SAH. SP600125, a c-Jun N-terminal kinase inhibitor, decreased neuronal injury and was associated with decreased caspase-3 activation and deoxyribonucleic acid damage, decreased aquaporin 1 upregulation and brain water, reduced matrix metalloproteinase 9 activation and collagen 4 degradation, and preservation of the blood brain barrier (BBB).
Effect of AVS on the beam balance test and BBB function were assessed in rats with single hemorrhage SAH. Continuous infusion of AVS, beginning 5 minutes after SAH, significantly improved BBB integrity, beam balance score and beam balance time 1 and 2 days after SAH and beam traverse time on days 1 to 4 (Table 2)[40]. Similar results were reported by Imperatore, et al. [14]. Other pharmacologic treatments that significantly improved beam balance scores for 1 to 3 days after single hemorrhage SAH were the calpain inhibitor, N-acetyl-leu-leu-methioninal [25] and felbamate [1]. Other investigators questioned the sensitivity of the beam balance test [29]. These investigators used endovascular SAH instead of cisterna magna single injection and the rats were randomly assigned to groups of control (intravenous 0.9% NaCl), moderately neuroprotective therapy (intravenous 7.5% NaCl) and highly effective neuroprotection (intravenous 7.5% NaCl + 6% dextran 70). The beam balance test employed differed from prior studies and comprised 2 wood rods (1.5 and 2.5 cm diameter) positioned horizontally 40 cm above a foam pad. Rats were placed on the center of each beam and the time they spent on the rod was recorded up to a maximum of 120 seconds. There were no differences between groups. Although no sham operated animals were included, rats were tested before SAH and there were only minimal deficits in the first 2 days after SAH.
The beam walking test differentiated placebo from treatment effects of AVS [24] and a calpain inhibitor [25] for 1 to 4 days post-SAH and felbamate treatment for 2 days [1]. Imperatore and colleagues did not find significant effects of AVS, however [14].
Some differences in results may be due to the model used. While the injection model may be more applicable to investigation of the direct effects of hemorrhage and delayed pathophysiological events like cerebral vasospasm, and hence more enduring behavioral deficits, the perforation model resembles human pathophysiology of aneurysmal rupture. The high mortality rate parallels the human situation and the model has been used to investigate early pathophysiological changes immediately after SAH. The subtle neurological alterations in the perforation model correlate with reports that neuronal death in the perforation model was seen in 11% of rats compared to 28% of rats undergoing cisterna magna injection SAH [16].
Correlation with Vasospasm
The pancaspase inhibitor z-VAD-FMK decreased TUNEL and caspase 3 in endothelial cells, decreased caspase 3 activation, reduced BBB permeability and brain edema, improved neurological outcome and decreased vasospasm after endovascular SAH [18]. Cahill and colleagues also reported better neurological scores, less brain edema and BBB breakdown, less vasospasm and less basilar artery apoptosis after treatment with pifithrin ∀ [20]. On the other hand, Takata, et al., used a double hemorrhage rat SAH model and found deficits in rotarod, vertical screen and balance beam, Morris water maze, as well as chronically decreased cerebral blood flow, neuronal loss in the hippocampus, and microvascular filling defects despite minimal proximal large artery vasospasm [39].
Therefore, there is some evidence that brain injury can occur after SAH without vasospasm. This is not surprising, nor are findings of a lack of correlation between vasospasm and any other endpoint. There are multiple pathways to poor outcome after SAH, only one of which is vasospasm (Figure 1). The relative importance of each will vary depending on the model and treatment may affect only one pathway [44]. Furthermore, the relationship may not be linear so simple statistical tests may not detect correlations.
What Other Tests Could be Used?
A limitation of most of the neurological tests used is they were developed to detect deficits produced by focal ischemia, usually of the middle cerebral artery territory. While this can occur after SAH, it is not common and more patients have deficits in neurobehavioral function, such as memory, visuospatial/construction ability and executive function than focal neurological deficits [45, 46]. Focal deficits are rare in animal models of SAH. Tests that would be more sensitive to the effects of SAH in animals could be selected based on regions of the brain known to be damaged after experimental SAH and/or based on deficits that occur more commonly after SAH in humans. Detailed evaluations of the regions of brain damaged after SAH in humans and experimental animals are sparse, however.
After SAH created by cisterna magna injection in rats, opening of the blood-brain barrier in cerebral cortex, brainstem and cerebellum was noted [47]. Vasospasm is most marked in the basilar artery and neuronal death may occur in the hippocampus and striatum [15, 16]. Cerebral blood flow reductions 15 minutes after SAH were diffuse but most marked in the brainstem and cerebellum [48]. Neuronal loss was reported in neocortex and hippocampal CA1 [39].
After SAH created by endovascular perforation, there also was diffuse opening of the BBB. Neuron apoptosis or increased messenger ribonucleic acid for proteins involved in apoptosis was reported in basal (orbital, cingulate, prefrontal) cortex [38, 49], hippocampus [50], CA1 [16] and Nissl staining showed neuronal injury in hippocampus (CA1 to CA3), motor cortex, caudoputamen and cerebellum bilaterally [28, 29]. The changes are greater on the side of endovascular perforation. Vasospasm was centered in the ipsilateral anterior circulation and reduced cerebral blood flow 15 minutes after SAH was bilateral and diffuse but most marked in the anterior circulation [48]. Findings were similar in the chiasmatic cistern injection model except that vasospasm is bilateral and severest in the anterior circulation, BBB changes are diffuse and neuronal injury was reported in prefrontal and cingulate cortex, thalamus, striatum and hypothalamus [16, 48]. In some studies, minimal neuronal injury occurs or it is only observed in some animals so it is likely that sensitive tests of neurobehavior would be required [38, 49].
Neurobehavior tests used in rodents have been used to assess attention, learning, memory and cognition (Table 6) [51–53]. The 5-choice serial reaction task and reaction time procedures measure attention, which is frequently impaired after SAH in humans [54]. Active avoidance conditioning paradigms, such as fear conditioning, may assess basal frontal lobe function, which may be damaged after SAH [55].
Several studies suggest memory is impaired after SAH [45, 46, 56]. The specific aspects of memory affected vary but many can be assessed in rodents [53]. Many paradigms are available for the Morris water maze [57]. Nonmatching (NMTS) and matching-to-sample (MTS) tests that can be spatial or non-spatial have been described and the time between trials can be delayed to test short-term memory [58]. Open field behavior also is used to assess neurobehavior. Frontal lobe function can be measured by the perceptual attentional set shifting task [59, 60].
It should be recognized that tests for specific neurobehaviors in humans are available and that just as classic neurological tests can localize various motor and sensory functions, sophisticated neurobehavior tests may localize to discrete brain regions. For example, ventromedial frontal cortex damage may be detected specifically by tests like the Iowa gambling task [61]. Marked abnormalities can occur when the minimental status examination is normal [62]. Tests that specifically test discrete areas of rodent cortex are less well documented. Some functions in humans and rodents, like anxiety and startle responses, may be mediated by diffuse neural networks. Another problem is that there is variability in the areas of the brain damaged by SAH so multiple tests might be needed but this is not easy to do in humans or experimental animals [46]. At this point it is difficult to make firm recommendations on what tests should be used in rodents with SAH. Preliminary choices might be those assessing attention, short-term working memory and basal frontal lobe function that probably involves olfaction in rodents and might be tested by perceptual attentional set shifting task.
Mice
Models
The 2 most commonly used models are the same as used in rats; single injection of blood into the cisterna magna or endovascular perforation [63–65].
Endpoints Used
Motor and sensory activity were assessed in the endovascular perforation model on a scale combined from 2 prior scales and comprised motor (spontaneous activity, symmetry of limb movements, climbing, balance and coordination for 0–12 points) and sensory (proprioception, vibrissae, visual, olfactory and tactile responses for 5–15 points, Tables 7 and 8)[30, 63, 66]. Mortality was not reported. There was significant weight loss 3 days after SAH compared to sham-operated animals. Neurological function was significantly impaired compared to sham-operated mice. Several variations of this scale were assessed 72 hours after endovascular SAH [67, 68]. It differentiated sham from SAH animals and also differentiated animals treated with simvastatin or vehicle [67] but not between wild-type and transgenic mice overexpressing human extracellular superoxide dismutase [68].
Mortality was reported in several mouse SAH models. Cisterna magna injection of autologous blood, 60:l, was associated with 4% mortality with no mortality mentioned for saline-injected animals [65]. In an endovascular perforation model, mortality (27 to 29%) did not differ between wild-type and human CuZn superoxide dismutase overexpressing transgenic mice [64]. Body weight changes have not been studied.
Mesis and colleagues studied rotarod performance and a neurological score also used by McGirt, et al., with minor differences in mice with perforation-induced SAH [69]. The neurological score was a subset of tests from a 48-point scale developed from prior scales for rats and mice [30, 70–73]. Mortality was not reported. Animals were tested before SAH and there appeared to be significant deficits in rotarod performance and neurological scores for 3 days after SAH.
Does Treatment of SAH Affect Neurological Tests and Correlate with Vasospasm?
Treatment of mice with perforation-induced SAH with high-dose carboxyamidotriazole, a voltage and nonvoltage-dependent calcium channel inhibitor, worsened rotarod performance, decreased vasospasm and was associated with a trend to worse neurological score whereas a low dose did not affect rotarod or neurological function or vasospasm compared to vehicle-treated animals [69]. Another series of mice were treated with 2 doses of nimodipine which improved neurological scores, rotarod latency and decreased vasospasm. There was about a 2% (2:m) mean diameter difference in vasospasm between the nimodipine doses that resulted in the effect on vasospasm being insignificant in the low-dose group. An apoE mimetic peptide, acetyl-AS-Aib-LRKL-Aib-KRLL-amide, administered alone or with nimodipine, also improved all 3 endpoints [74]. Several interpretations are possible. One is that carboxyamidotriazole has toxic effects at high doses that worsen behavior. The beneficial effects of nimodipine may be separate or in addition to decreasing vasospasm [75]. ApoE mimetic peptides were neuroprotective in other brain injuries and may decrease vasospasm via antiinflammatory mechanisms [74]. In support of this, the same behavior endpoints were assessed in mice that express only human APOE3 or APOE4 [74]. After SAH created by endovascular perforation, mice with APOE3 had better rotarod performance and less vasospasm compared to APOE4 mice. An ApoE4 peptide mimetic administered to wild-type mice after SAH reduced mortality and improved neurological score, rotarod latency and vasospasm.
Another report from the same laboratory found that levetiracetam had the same pattern of effects in that it improved all 3 measures in high doses in SAH mice [76]. Levetiracetam may be neuroprotective and antivasospastic by virtue of its ability to inhibit voltage-dependent calcium, (-aminobutyric acid and glycine currents [76].
What Other Tests Could be Used?
Few studies have examined areas of brain injured after SAH in mice. Learning, memory and neurobehavior assessment in mice, while not identical, is similar to in rats and has not been assessed yet after murine SAH. Recommendations would probably be similar to those for rats.
Rabbits
Models
This is limited to cisterna magna injections of blood once or twice [77, 78]. SAH has been combined with ligation of the carotid arteries in an attempt to induce cerebral ischemia from vasospasm [79].
Endpoints Used
Endo, et al., ligated both common carotid arteries and 2 weeks later induced SAH by injecting blood into the cisterna magna of rabbits (Table 9)[79]. Neurological deficits were categorized as normal, minimal or suspicious neurological deficit, mild deficit without abnormal movement or severe neurological deficit with abnormal movement. 5 of 13 animals had mild dysfunction after carotid ligation and this was more severe after SAH and more severe than in animals with SAH alone. Subtle transient decrements in neurological function were detected in rabbits with SAH treated with intravenous anticardiolipin antibodies compared to those with SAH alone [80]. Whether nimodipine and ecdysterone improved neurological function on this scale in another study was difficult to discern from the paper [81]. A more complicated model added, in addition to bilateral carotid occlusion and SAH, oxyhemoglobin cisternal injection 2 days after SAH [82]. No correlation between vasospasm and neurological score was detected although the degree of vasospasm was similar for grades 2 and 3 and worse for grade 4.
Mortality and open-field locomotor activity were assessed after single SAH in rabbits and compared in animals given intravenous saline or erythropoeitin [77]. No animals underwent sham surgery. Mortality was reduced significantly after SAH when erythropoeitin was administered. Open-field locomotor activity was assessed by number or rearings and a measure of the amount of movement about an open field apparatus and was improved also with erythropoeitin.
The 6-point scale developed for dogs was applied to rabbits with SAH created by one or 2 injections of blood into the cisterna magna [78]. The only significant difference was the appetite score was significantly higher 3 days after double SAH compared to single hemorrhage. There were no saline-injected controls.
Mortality rates and weight changes are not well-described in rabbit models of SAH. One group reported 40% mortality after single cisternal injection SAH in rabbits compared to 0% after saline injection [83] and another had 0% after single and 6% after double injection SAH [78].
Another neurological scale developed to assess myelopathy in rabbits was applied to rabbits undergoing SAH. The scores were significantly worse in animals with severe delayed vasospasm compared to those with mild vasospasm or sham surgery [83]. The neurological functions evaluated were posture, gait, and righting reflexes (each given a score of 0 for normal, 1 for mild impairment, 2 for moderate impairment and 3 for severe impairment. Front and hindlimb reflexes were scored 0 for normal, 1 for brisk, 2 for spreading and 3 for clonus.
Does Treatment of SAH Affect Neurological Tests and Correlate with Vasospasm?
There were no reports of a lack of relationship between the severity of vasospasm and neurological function in rabbit models of SAH.
What Other Tests Could be Used?
Some other tests used in rabbits include eyeblink conditioning and the discriminative avoidance/approach task [84, 85]. Open field activity was assessed in one study already [77, 86]. The disadvantages of using a rabbit model of SAH would be that there are fewer behavior tests, in addition to limited availability of specific molecular biological reagents for assessing other endpoints.
Dogs
Models
SAH has been produced most commonly by one or 2 injections of blood into the cisterna magna.
Endpoints Used
Several studies assessed neurological function within hours of SAH or used only broad qualitative assessments (Table 10) [87–89]. A single injection model in dogs used a 6 point neurological function scale. There were no saline-injected controls. Some nonsteroidal antiinflammatory drugs decreased vasospasm 24 hours after SAH and improved scores on this scale [89, 90]. Other similar scales including a dog coma score did not detect deficits after SAH in dogs [91, 92].
The most widely used scale assessed appetite, activity and neurologic deficits in the double injection model [93–98]. Appetite was graded as finished meal = 2, left meal unfinished = 1, scarcely ate = 0. Activity was graded as active, barking or standing = 2, lying down, will stand and walk with some stimulation = 1, almost always lying down = 0. Neurological deficits were graded as no deficit = 2, unable to walk because of ataxia or paresis = 1, impossible to walk or stand because of ataxia or paresis = 0. We could not find reports of whether the scale differentiates saline-injected controls from SAH. Mortality is seldom reported but is low in this model and not significantly different between SAH and saline-injected controls (R.L. Macdonald, personal observation). Weight has not been used as an endpoint. The scale detected significant improvement in appetite and activity after treatment with mitogen associated protein kinase inhibitor [93]. Caspase inhibitors Ac-DEVD-CHO and Z-VAD-FMK improved appetite within 3 days of SAH and produced variable improvements in activity [99]. These results confirm rat studies suggesting inhibition of endothelial cell apoptosis decreases vasospasm.
Other treatments that were associated with similar improvements were inhibitors of Ras FTase [100], JNK [101] and p53 [102], again supporting a role for apoptosis and signal transduction in the artery wall mediating vasospasm. The neurological deficit portion of the scale was almost never affected.
Does Treatment of SAH Affect Neurological Tests and Correlate with Vasospasm?
No relation between neurological deficits measured on a 6-point scale and vasospasm was claimed although there was a general increase in vasospasm with worsening neurological score [89, 90]. The scale also is altered by pain that would be reduced by the drugs independent of any effects on vasospasm or brain injury.
U-0126 improved behavior but vasospasm was not decreased [93]. U-0126 is a mitogen-activated protein kinase kinase inhibitor that decreases arterial contractions to endothelin and erythrocyte hemolysate. The authors hypothesized that neuroprotective effects might account for the improved behavior.
What Other Tests Could be Used?
In the single and double-hemorrhage models, vasospasm is most severe in the basilar artery and less marked in the anterior circulation [103]. One study noted caspase-3 and glial fibrillary acidic protein in astrocytes and neuronal injury were most marked in the hippocampus, second in the cortex and least in the brainstem in the double-hemorrhage dog model [104]. Tests of learning and memory might therefore be worth assessing in this model. There are numerous sophisticated neurobehavior tests available for dogs, including open field behavior, object discrimination tasks often with reversal tasks and various permutations of immediate and delayed nonmatching-to-sample tests [52, 105]. These assess attention, executive function, complex learning and spatial learning and are sensitive to aging and interventions [106–108].
Summary and Future Directions
High mortality is a characteristic of SAH in humans and it has been assessed after SAH in rats and mice in several models and is higher after SAH than sham-surgery (Table 11). This endpoint is not well-described in rabbits and dogs. Mortality is low in the dog double hemorrhage model because significant vasospasm can be produced without having to produce an injury severe enough to be fatal. Several treatments have reduced mortality in rodent SAH models and this endpoint should be reported and probably included in outcome analysis.
Body weight decreases after SAH in rats and mice but has not been assessed in other animal models. These decreases can also be mitigated by treatment in some cases. Neurological scales testing motor, sensory and reflex functions have been mainly used in rats, mice and dogs and can detect effects of SAH although the differences are often small and transient. Rotarod, beam balance and beam walking tasks have not been widely used and when they have, again often small, transient effects are seen both comparing SAH to sham-operated animals and in detecting treatment effects. Neurobehavioral tests have only recently been reported in rats and the results are conflicting with one group showing robust effects and another only minor differences [38, 39]. Different models were used and the results were markedly different.
There are other neurobehavioral tests that assess neurobehavior in rodents, dogs and other species [41, 58, 109]. Neurobehavioral deficits in humans with SAH have been reported [110–112] but they need to be reviewed in detail so tests that assess these deficits in animal models can be used. The purpose would first be to be able to use animal models to predict whether a treatment would work in humans. This is a problem now in stroke research because a drug is tested in rodents and determined to decrease infarct size or neuronal damage and then it is tested in humans and has no effect. The trials in humans are costly and time-consuming so a better method to correlate outcome in animals and humans might facilitate testing of the most potentially efficacious treatments in humans. Second, better understanding of the pathogenesis of the disease, such as SAH in this case, hopefully would be forthcoming. For example, it is still unclear why neurobehavior is affected after SAH and whether this is due to increased intracranial pressure, SAH or a combination.
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Supported by grants from Physicians Services Incorporated Foundation and the Brain Aneurysm Foundation.
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HJ reviewed the literature and wrote the first draft of the paper. JA revised the first draft and searched the literature. MS, AT, XS and GC read the manuscript, searched the literature and contributed to the second draft. RLM formulated the idea, searched the literature, basically rewrote the second draft, formatted the manuscript and submitted it.
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Jeon, H., Ai, J., Sabri, M. et al. Neurological and neurobehavioral assessment of experimental subarachnoid hemorrhage. BMC Neurosci 10, 103 (2009). https://doi.org/10.1186/1471-2202-10-103
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DOI: https://doi.org/10.1186/1471-2202-10-103