Differential evolution patterns in brain temperature in
different ischemic tissues in Monkey Middle Cerebral
Artery Occlusion Model 112115 SUN Zhihua, ZHANG Jing, CHEN Yingmin, ZHANG Xuejun, ZHANG Yunting, 11GUO Hong, YU Chunshui
(1. Department of Radiology , Tianjin Medical University General Hospital, TianJin 300052; 2. Department of Radiology, The People Hospital of Hebei Province, ShiJiaZhuang 050005) Abstract: Objectives: Brain temperature was elevated in acute ischemic stroke, especially in ischemic
10 penumbra (IP). We try to investigate the dynamic evolution of brain temperature in different ischemic
s: The middle cerebral artery occlusion (MCAO) and recanalization regions in monkey models. Method
model was successfully established in 4 monkeys. Brain temperature of different ischemic regions was measured by Proton magnetic resonance spectroscopy (1H MRS), and then the evolution processes of brain temperature were compared among different ischemic regions. Results: The normal (baseline)
15 brain temperature of monkey brain was 37.16?. At artery occlusion stage, the mean brain temperature
of ischemic tissue was 1.16?higher than that of the baseline, however, this increase is region-dependent with 1.72? in IP, 1.08? in infarct core and 0.62? in oligemia region. After recanalization, the brain temperature of infarct core showed a pattern of an initially decrease accompanied by a following increase. However, the brain temperature of IP and oligemia region
20 showed a monotonously and slowly decreased pattern. Conclusion: The infarct core and IP have different evolution patterns of brain temperature, which suggests that in vivo measurement of brain temperature could be help to identify whether ischemic tissue is survival.
Keywords: Ischemic stroke; brain temperature; ischemic penumbra; Magnetic Resonance Spectroscopy
Elevation in brain temperature was common in acute ischemic stroke and associated with a
[1-3]worse outcome . One potential explanation is that pyrexia would increase brain temperature and the brain metabolic rate, could result in more rapid exhaustion of limited energy and oxygen
30 supplies, and increased production of free radicals and other toxic substances in ischemic tissue [4,5]. For different blood flow and metabolic state, brain temperature would be different in different regions of ischemic tissue, i.e. infarct core, ischemic penumbra (IP) and oligemia region.
Conventional methods of measuring brain temperature by invasive probes could monitor only
[6,7]one or a few locations simultaneously and cursorily, and was difficult to be accepted clinically .
35 Several magnetic resonance parameters can be used for the noninvasive measurement of regional temperatures, including the diffusion coefficient, the longitudinal relaxation time constant (T1)
[8,9]and the proton resonance frequency (PRF), and the latter is more popular . MR spectroscopic
techniques are, in principle, capable of estimating absolute temperatures. So it is possible to measure brain temperature more accurately in different regions of ischemic lesion, especially in
Many experimental and clinical study have been focus on the brain temperature in the fields
[6,10,11]of cerebral infarction measured by MRS . Brain temperature was elevated in ischemic brain
soon after stroke, prior to any increase in body temperature, and was significantly higher in
[2,12] probable penumbral tissue than in infarct core or normal brain . A previous study found
45 that there was significant difference of brain temperature between ischemic tissue and
Foundations: National Doctoral Fund of Ministry of Education？No.20091202110006？
Brief author introduction:SUN Zhihua, (1976-), female,Ph.D.,main research:neuroimaging.
Correspondance author: ZHANG Yunting, (1946-), male,Ph.D., main research: neuroimaging. E-mail:
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contralateral normal hemisphere in patients with middle cerebral artery occlusion. And brain
temperature of ischemic tissue would increase with the enlargement of lesion volume. However,
there have been no reports of detailed evolution of brain temperature in different regions of
ischemic lesion at early stage of onset.
50 In this work, we modified the equations to measure brain temperature based on MRS PRF
techniques in a physiological solution, and used the final equation to calculate brain temperature
of different regions in ischemic lesion before and after reperfusion, especially IP, in monkey
middle cerebral artery occlusion (MCAO) models.
1 Materials and Methods
55 1.1 Animal Model
The experiment was approved by Animal Care and Use Committee of Tianjin Medical
University. Six mature male monkeys (Cynomologous macaque) with a mean weight of 8.5kg
(range from 8 to 10 kg) were supplied by Experimental Animal Center of Beijing Military Medical
The MCAO model was established by an autothrombus interventional method. Blood 60
pressure, heart rate, respiration and degree of blood oxygen saturation were monitored. After a
selected monkey was anaesthetized generally and sterilized locally in right inguinal region, the
right femoral artery was separated and punctured, and then the 5F catheter sheath and the 4F
catheter were placed in. One side of the middle cerebral artery (MCA) that is more suitable for the 65 autothrombus interventional method was chosen according to the bilateral vertebral and internal
carotid arteries angiography. Then a 3F-SP catheter was induced to the artery through the 4F
catheter, and positioned in the MCA. We pulled and rotated the 3F-SP catheter to induce
thrombosis. After 20~30 minutes, we pull out the 3F-SP catheter and remain the 4F catheter, then
MRI and MRS in artery occlusion stage were performed. About 1.5-2 hours after occlusion, we 70 induced the 3F-SP catheter again and injected 50ml of saline solution with 2000 units of heparin
and 25 million units of urokinase to make the artery recanalized. Finally, we pulled out the
catheters and ligated the right femoral artery. The monkeys maintained an anaesthetized state
during MRI and CT examinations.
1.2 MRI and MRS Examination
75 MRI and MRS was performed with a GE 1.5T Twin Speed Infinity with Excite I magnetic
resonance system, 1h after occlusion to 1h, 3h, 6h, 12h and 24h after recanalization consecutively.
In addition, MRS was also performed before occlusion to acquired normal brain temperature. We
performed DWI, PWI and T-weighted imaging (TWI) with a head coil. TWI parameters 222
included: repetition time (TR) = 4000 ms; echo time (TE) = 106.4 ms; averages = 2; slice 80 thickness = 2.5mm; gap = 0mm, FOV = 18cm×18cm, matrix = 288×256. DWI was obtained using
a single shot spin-echo echo planar sequence, with TR = 6000 ms; TE = 96.8 ms; averages = 2; b
2= 1000s/mm; FOV = 18cm×18cm, matrix = 128×128. PWI was obtained using a single shot
gradient recalled echo planar imaging T*WI sequence, i.e., dynamic susceptibility contrast (DSC) 2
MRI, with TR = 2000 ms; TE = 80 ms; averages = 1; FOV = 18cm×18cm, matrix 128×128. A 85 Gd-DTPA bolus (0.1mmol/kg) was administered by power injector at a rate of 2ml/s, and then 10
ml of isotonic saline was injected to wash the pipe. A total of 330 slices were acquired.
We used muli-voxel Point Resolved Spectroscopy (PRESS)-localized proton MRS with the
voxel grid centered on the slice showing the maximum ischemic lesion on DWI. The imaging
parameters were: TR=1500 ms, TE=135 ms, FOV = 18cm×18cm, matrix = 24×24, slice thickness
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90 = 10mm, total acquired time=9’6”. The voxel grid (1ml) was carefully placed within brain to
include as much of the visible ischemic lesion, ipsilateral and contralateral normal brain as possible and to avoid contamination of the spectra with lipid signal from bone marrow or
subcutaneous fat. Almost thirty available voxel grids were obtained. We collected standard three-pulse chemical shift selective (CHESS) water suppression and non-suppression imaging.
Spectroscopic data of water suppression was obtained with 99% of suppression level. 95
1.3 Brain Temperature Calculation
Spectroscopic data was dealt with Java-based magnetic resonance user interface (jMRUI,
http://www.mrui.uab.es/mrui) package, one spectroscopic time domain analysis software. At first,
perform the zero-order phase correction of water proton peak (effectively bringing water to a
chemical shift of 4.70 ppm), then remove the residual water signal using the Hanckel-Lanczos 100
Singular Value Decomposition (HLSVD) method. Spectroscopic data were Fourier transformed for display and visual quality control purposes by using Advanced Method for Accurate Robust and Efficient Spectral Fitting (AMARES) algorithm within the jMRUI package. Gaussian components were modeled in the time domain, including choline (Cho), creatine (Cr), N-acetyl
aspartate containing compounds (NAA) and lactate (Lac). The chemical shifts (i.e. frequency) of 105
the fitted metabolite peaks were reported to a precision of 0.001 ppm to confirm the chemical shifts of NAA. Spectra were automatically discarded if fitted line widths were less than 1Hz or greater than10 Hz. We inspected the spectroscopic data visually and discarded the voxels laying on the edges of the PRESS excitation region, coming from voxels containing CSF and with poor
quality, e.g. having a badly elevated baseline or containing spurious peaks. 110
Temperature T is derived from the chemical shift of water (CS) using a relation of the H2O form: T = T+ k(CS- CS) (1) ref H2Oref CSis the (temperature-independent) chemical shift of a reference compound, k is the ref
coefficient of proportionality and Tis the reference temperature. Temperature-dependent 115 ref changes in hydrogen bonding cause the water chemical shift to vary linearly with temperature at
0.01ppm per ?. In our scanner, with 4.7ppm as the chemical shift of water and 37? as the referent temperature, Eq.(1) was changed to Eq.(2):
T =37 + 100(CS- CS) (2) NAANAAref
CSis the apparent chemical shift of NAA and CSis the reference chemical shift of 120 NAA NAAref
NAA. We measured the temperature of a physiological solution (NAA 12.5 mMol, Cr 10.0 mMol
and Cho 3.0 mMol) within a constant temperature equipment to acquire the CS, which could NAAref
be fit for MR scan. There was a linear correlation between the PRF and the temperature of solution ranged from 34? to 44? and the value of was 2.039ppm by this method. So CS NAA ref
125 Eq.(3) was used to calculate the brain temperature of each voxel grid in our study.
T =37 + 100(CS- 2.039) (3) NAA 1.4 Definition of different ischemic regions Mean Transit Time (MTT) map of PWI was processed by perfusion software using a GE Sun
AW4.2 workstation. And the final infarct lesion was defined as abnormal signal intensity on TWI 2
at 24h of reperfusion stage. We classified the ischemic lesion (abnomal signal intensity on MTT) 130
into three kinds of tissue by DWI and MTT at artery occlusion stage and TWI at 24h of 2
reperfusion stage: infarct core with high signal intensity on both DWI and TWI, IP with high 2
signal intensity on DWI but normal on TWI, and oligemia region with normal signal intensity on 2
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WI, but abnormal signal intensity on MTT (Figure.1). If one kind of tissue was both DWI and T2
135 beyond 75% within one voxel grid of MRS, we named the voxel grid as this kind of tissue. Calculate brain temperature of each voxel grid and the mean and standard deviation of brain
temperature for each tissue voxel category. Figure.1. Definition of different ischemic regions. DWI (a) and MTT (c) at artery occlusion stage, T2WI (b) at 24h are used to define infarct core, IP and oligemia region. On the localized DWI of MRS (d), the red line marks the 140 abnormal perfusion region, the yellow line shows the region with abnormal diffusion, and the white line denotes the abnormal region on T2WI at 24h, i.e., infarct core. IP is the region between the yellow and white lines, while oligemia region is between the red and yellow lines.
1.5 Statistical Analysis 145 Statistical analysis was performed with the SPSS 11.0 software package. Differences were considered statistically significant at P < 0.05. Paired t test was used to analyze the differences of
brain temperature between normal bilateral hemispheres, and between different ischemic regions and contralateral brain. One-way ANOVA was performed among the brain temperature of three
kinds of tissues. 150
2 Results 2.1 Normal brain temperature of monkey The normal (baseline) brain temperature of six monkeys were measured before operation (Table.1). The mean baseline brain temperature was 37.16? in left hemispheres, 37.17? in right hemispheres and 37.16? in bilateral hemispheres. There was no statistical difference in the 155 baseline brain temperature between the bilateral hemispheres revealed by paired t test (t=-1.659，
P>0.05). Table.1. Normal brain temperature of monkeys ？Temperature？? No.Left hemisphere Right hemisphere 1 37.05 (0.26) 37.07 (0.27) 2 37.13 (0.36) 37.11 (0.38)
3 37.26 (0.26) 37.28 (0.23)
4 37.12 (0.24) 37.15 (0.25) 5 37.23 (0.18) 37.24 (0.21)
6 37.16 (0.28) 37.17 (0.24)
Note: Data are expressed by means (standard deviation).
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160 2.2 Evolution of brain temperature in monkey MCAO and reperfusion models MCAO models were successfully established in four out of the six monkeys, including one right and three left sides. Table.2 showed the brain temperature of different ischemic tissues and contralateral hemisphere at artery occlusion stage (0h) and different time points of reperfusion stage. At artery occlusion stage, mean brain temperature of ischemic tissue was 1.16? higher
than baseline brain temperature. The increase in brain temperature is region-dependent with 1.72 165 ? in IP, 1.08 ? in infarct core and 0.62 ? in oligemia region compared to basal brain temperature. At reperfusion stage, the evolution of brain temperature differed in infarct core, IP and oligemia region (Figure.2). After recanalization, the brain temperature of infarct core showed a pattern of an initially decrease accompanied by a following increase. However, the brain temperature of IP and oligemia region showed a monotonously and slowly decreased pattern. The 170 brain temperature of contralateral hemisphere increased slightly (0.23?) compared to the baseline
brain temperature. Table.2 The brain temperature of different ischemic tissues and contralateral hemisphere at artery occlusion stage (0h) and different time points of reperfusion stage in monkey MCAO model 175 ？Temperature ？? Time after Contralateral modeling(hours) Infarct core IP Oligemia region hemisphere
37.46 (0.14) 0 38.26 (0.27) 38.90 (0.19) 37.80 (0.14) 37.37 (0.46) 1 37.81 (0.26) 38.34 (0.38) 37.92 (0.34) 37.41 (0.37) 3 37.21 (0.36) 38.29 (0.23) 37.79 (0.33)
37.31 (0.32) 6 37.26 (0.29) 38.22 (0.25) 37.59 (0.35)
37.33 (0.39) 12 38.48 (0.17) 37.56 (0.28) 37.49 (0.38)
24 38.63 (0.19) 37.47 (0.35) 37.29 (0.35) 37.28 (0.45)
Note: Data are expressed by means (standard deviation).
Figure.2. Evolution of brain temperature of different ischemic regions and contralateral hemisphere at artery
occlusion stage (0h) and reperfusion stage in monkey MCAO model. 180 Table.3 showed the differences of brain temperature between different ischemic tissues and contralateral hemisphere. There were significant differences of brain temperature between infarct core and contralateral hemisphere at 0h, 1h, 12h and 24h, between IP and contralateral hemisphere
within 6h, between oligemia region and contralateral hemisphere within 3h (P<0.05), while no 185
significant differences were found between infarct core and contralateral hemisphere at 3h and 6h,
between IP and contralateral hemisphere at 12h and 24h, between oligemia region and
contralateral hemisphere at and after 6h (P>0.05).
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Table.3 Paired t test of brain temperature between different ischemic tissues and contralateral hemisphere in
monkey MCAO model (t value)
IP & Oligemia region & Time (h) Infarct core & contralateral
hemisphere contralateral hemisphere contralateral hemisphere 0 5.383* 9.69* 2.788* 1 2.961* 6.527* 3.028* 3 5.922* 2.557* ！1.346 6 6.124* 1.884 0.336 ！ 12 7.739* 1.548 1.077 24 9.085* 1.279 0.067
Note: * represents P<0.05 200 2.3 Differences of brain temperature among different ischemic regions One-way ANOVA was performed on the brain temperature among different ischemic tissues
at different time points (Table.4). There were significant differences in the brain temperature among different ischemic tissues at each time point (F values were 27.64, 8.32, 26.46, 21.55,
205 27.64 and 47.90 at 0h, 1h, 3h, 6h, 12h and 24h, respectively, P<0.05). Bonferroni method was
used for post hoc comparisons. There were significant differences in brain temperature between infarct core and IP at each time point, between IP and oligemia region within 6h, between infarct
core and oligemia region at 0h, 3h, 12h and 24h (P<0.05), while there were no significant differences between IP and oligemia region at 12h and 24h, between infarct core and oligemia
region at 1h and 6h (P>0.05).210
Table.4 ANOVA among brain temperature of different ischemic tissues and contralateral hemisphere in monkey
MCAO model (P value) Infarct core & oligemia Time(h) Infarct core & IP IP & oligemia region region .005* 00 0.032* 0.007* 0.287 1 0.004* 0.005* 0.011* 3 0.003* 0.013* 0.346 6 0.001* 0.011* 0.035* 12 0.001* 0.078 0.024* 24 0.001* 0.135 Note: * represents P<0.05 215
3 Discussion Previous studies of brain temperature were limited by reliance on invasive measurement [14-17] techniques, such as inserted probes in brain tissue . In this situation, brain temperature could be lower than actual temperature for the brain surface was exposed to cooler environment air.
220 Invasive techniques may inevitably induce local microlesions and inflammatory response adjacent
to probes, which possibly affects brain temperature. Infrared thermometry is a non-invasive method, but it fails to measure the deep brain temperature due to the limited depth penetration and
cannot make an accurate localization because of the limited spatial resolution of this method. MRS is a validated method for measuring brain temperature non-invasively using the principle that [8,10,18]water frequency shift relative to N-acetyl aspartate is temperature-dependent . Moreover, 225
MRS thermometry could avoid most of the above-mentioned weaknesses of other methods. Since equations for calculating brain temperature (especially the CS) were dependent on NAAref
the MR scanner and sequence parameters, the temperature equation was modified based on in vivo models or healthy volunteers . In our study, we used a physiological solution within a constant
temperature equipment to acquire the CS. So the CSwas more accurately to calculate NAArefNAAref 230
the brain temperature.
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There are also several limitations about MRS thermometry. The signal intensity from NAA
as a chemical shift reference should be high enough for calculating the temperature. However, the Nually after stroke, as a consequence, studies of temperature of ischemic brain AA decreases grad . Another limitation is the environmental tissue by MRS should be limited at acute stoke 235 temperature of MR scanner. In most scanners, it should be 18~20 ? perennially. Brain  temperature would be lower after long-time examination. A previous study found that there was a statistically significant reduction in temperature of 0.09? per scan (P = 0.0001) across the
four sequential MRS scans on 4 normal volunteers, presumably due to cooling by the air current in the bore of the magnet (or relative cerebral inactivity during the scan). In our study, MR 240
examination was arranged as DWI, TWI, PWI and MRS for 15min for all the time points, which 2 can at least partly reduce effect of environmental temperature on the longitudinal changes of brain
temperature. Perfusion state is critical for the temperature in brain tissue, for example, reduced blood flow could impair heat exchange and result in a higher temperature in ischemic tissue . According the 245
perfusion state theory, the brain temperature in the infarct core should increase highest because of the lowest blood flow. However, we found that the highest increase of brain temperature was in the IP, then the infarct core, and finally the oligemia region at artery occlusion stage in monkey
MCAO model. This finding suggests that the perfusion state was not the only factor for brain temperature elevation in ischemic tissue, and other factors might play a role. 250
Brain tissue temperature is mainly determined by two processes, heat production and heat
radiation. In infarct core, both the reduced blood flow induced the reduction of heat radiation and the increased anaerobic metabolism induced the increase of heat production may result in the
elevated brain temperature. In IP tissue, the reduced blood flow may induce the reduction of heat radiation, while the increase in heat production was induced by the following events, including 255 [19-22]both the aerobic and anaerobic metaboli sm , inflammation and the releasing of excitatory [23,24] amino acids . These complex processes may account for the higher elevated brain temperature in IP than in infarct core or oligemia regions at artery occlusion stage. In addition,
[25-28]uncoupling protein 2 (UCP-2) is a natural neuroprotective factor in human ischaemic brain . UCP-2 up-regulation may regulate ATP synthesis by uncoupling oxidation from phosphorylation, 260 thus dissipate energy as local heat, and simultaneously be responsible for the early rise in lesion
brain temperature after stroke. The brain temperature in the contralateral hemisphere (which may be more closely related to
body temperature) elevated slightly after stroke reflecting increased neuronal activity in response to the ischemia . So in our study, the brain temperature in ischemic region was evaluated by 265 comparing with that of the baseline brain temperature is more reasonable than the previously used
method that regarded the brain temperature of contralateral hemisphere as a control state. In the present study, we focused on the detailed changes of brain temperature of different 1 ischemic tissues before and after reperfusion by H MRS. We found that the IP and infarct core showed different evolution patterns of brain temperature, which may provide us a method to 270 identify IP from infarct core. But our study also had some limitations. The first limitation is that
the classification of different ischemic tissues in our study was based on DWI and PWI at artery occlusion stage and TWI at 24h of reperfusion stage. IP was defined as the low-perfusion tissue 2
with high signal intensity on DWI but normal on TWI, but it may miss part of the IP tissue 2[29-31] peripheral to the DWI abnormal regions . The second one is the relatively small sample size 275 of our study. The last one is that we do not know whether our results obtained from monkey
MCAO model can be generalized to the human stroke patients. Further studies are needed to
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overcome the above limitations and to clarify the mechanism underlying the evolution of brain temperature of ischemic tissue.
280 4 Conclusion After ischemic stroke, the infarct core and IP have different evolution patterns of brain temperature, which suggests that in vivo measurement of brain temperature could be help to identify whether ischemic tissue is survival.
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1121111 的研究 孙志华，张敬，陈英敏，张雪君，张云亭，郭宏，于春水 355 ？1. 天津医科大学总医院放射科，天津 300052(
2. 河北省人民医院，石家庄 050005？ 摘要，目的，急性缺血性 脑梗死脑温会增高，特别是缺血半暗带区？IP？。本文研究了猴脑 缺血模型不同缺血区的脑 温动态变化。方法，4 只猴成功制作了大脑中动脉闭塞？MCAO？ 和再通模型。采用 1H MRS 的方法测量脑温，比较缺血不同区域的脑温变化。结果，正常 猴脑平均脑温为 37.16?。动脉闭塞期，脑缺血组织平均增高 1.16?，不同缺血组织增高幅 度不同，IP 增高 360 1.72?，梗死核心增高 1.08?，良性灌注减少区增高 0.62?。再通后，梗 死核心区脑温先 下降而后增高，IP 和良性灌注减少区脑温逐渐下降接近正常。结论，梗死 核心和 IP 具有 不同的脑温演变模式，提示脑温可监测脑组织是否存活。 关键词，缺血性脑梗死(脑温( 缺血半暗带(磁共振波谱 中图分类号，R445.2
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