DIFFUSION-WEIGHTED MAGNETIC RESONANCE IMAGING OF THE NORMAL CANINE BRAIN ¨ ANTJE HARTMANN, CHARLOTTE SOFFLER , KLAUS FAILING, ANDREAS SCHAUBMAR, MARTIN KRAMER , MARTIN J. SCHMIDT Diffusion-weighted imaging (DWI) MRI has been primarily reported as a method for diagnosing cerebrovascular disease in veterinary patients. In humans, clinical applications for diffusion-weighted MRI have also included epilepsy, Alzheimer’s, and Creutzfeld–Jakob disease. Before these applications can be developed in veterinary patients, more data on brain diffusion characteristics are needed. Therefore, the aim of this study was to evaluate the distribution of diffusion in the normal canine brain. Magnetic resonance imaging of the brain was performed in ten, clinically normal, purpose-bred beagle dogs. On apparent diffusion coefficient maps, regions of interest were drawn around the caudate nucleus, thalamus, piriform lobe, hippocampus, semioval center, and cerebral cortex. Statistically significant differences in mean apparent diffusion coefficient were found for the internal capsule, hippocampus, and thalamus. The highest apparent diffusion coefficient (1044.29 ± 165.21 µm2 /s (mean ± SD (standard deviation)) was detected in the hippocampus. The lowest apparent diffusion coefficient was measured in the semioval center (721.39 ± 126.28 µm2 /s (mean ± SD)). Significant differences in mean apparent diffusion coefficients of the caudate nucleus, thalamus, and piriform lobe were found by comparing right and left sides. Differences between brain regions may occur due to differences in myelination, neural density, or fiber orientation. The reason for the differences between right and left sides remains unclear. Data from the current study provide background for further studies of diffusion changes in C 2014 American College of Veterinary Radiology. dogs with brain disease. Key words: brain, diffusion-weighted imaging, dog, MRI, magnetic resonance imaging.
ferences in tissue architecture limit the movement of water molecules in one or more directions, which is termed anisotropic diffusion.1–4 The brain white matter shows a high degree of such anisotropy. Fiber bundles in white matter allow unrestricted diffusion in the longitudinal course of the axon, but the axonal membrane and neurofibrils limit diffusion perpendicular to this.2,4 A measure of the mobility of molecules is the diffusion coefficient; this is a proportional constant used to calculate the thermal transport of a substance based on diffusion. In the brain, the measured diffusion results from the movement of water molecules in three compartments—intravascular perfusion, extracellular diffusion, and intracellular diffusion. In vivo, pure diffusion cannot be easily separated from other sources of water mobility. In the clinical setting, water motion is therefore called the apparent diffusion coefficient (ADC).5–7 Diffusion weighted imaging has been reported to be used predominantly for diagnosis of cerebrovascular accidents in veterinary medicine.8–10 However, one study described its potential use in differentiating neoplastic, inflammatory, hemorrhagic, and ischemic brain diseases.11 In human medicine, DWI has been proven to be valuable in the evaluation of a wide variety of other disease processes, in which the molecular motion of water can be substantially altered. In this context, the use of DWI in patients with
(MRI) is widely used in veterinary medicine, the interpretation of images is focused on structural changes of the brain parenchyma. However, many diseases of the central nervous system do not cause pathological changes that are detectable using conventional pulse sequences. Functional MRI, which includes diffusion-weighted imaging (DWI), offers the possibility to visualize physiological processes inside the brain tissue. Diffusion weighted imaging represents a noninvasive technique that allows the visualization of diffusion of water molecules in vivo.1,2 Diffusion is based on Brownian motion of water molecules.2,3 The average distance a water molecule moves corresponds to the dimension of the tissue elements. If diffusion is unrestricted and the movement of molecules is identical in all directions, the diffusion is called isotropic. Regional difLTHOUGH MAGNETIC RESONANCE IMAGING
From the Department of Veterinary Clinical Sciences Small Animal Clinic, Justus Liebig-University, Frankfurter Straße 108, 35392 ¨ Giessen, Germany (Hartmann, Soffler, Kramer, Schmidt) and Unit for Biomathematics and Data Processing, Faculty of Veterinary Medicine, Justus Liebig-University, Frankfurter Straße 95, 35392, Giessen, Germany (Failing, Schaubmar). Address correspondence and reprint requests to Antje Hartmann, at the above address. E-mail: [email protected]
Received September 16, 2013; accepted for publication January 17, 2014. doi: 10.1111/vru.12170
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epilepsy is one of the most interesting applications.12–16 The diffusion changes observed might vary depending on the epileptogenic process. Increased ADC values could be found in the hippocampus of patients with temporal lobe epilepsy in comparison with healthy volunteers. Epileptic foci in the neocortical aspect of the brain have also been shown to have increased ADC values in humans. This is considered to be the result of an enlargement of the intercellular spaces caused degenerative neuronal loss due to hippocampal atrophy.17 Kainic acid induced complex partial status epilepticus lead to a reduction in ADC values. The most likely pathophysiological processes are excitotoxic leading to cell swelling reducing the space for diffusion. Therefore, the detection of changes is based on the comparison of the right and left side of certain brain areas (e.g. hippocampus, thalamus, cerebral cortex, pulvinar nuclei).13,17,18 Changes after seizures are short-lived and are best detected within 30 min after onset. Nevertheless changes in the ADC of 7%–30% can be detected up to 24 h after onset and sometimes even longer. Unfortunately, studies examining the progression of diffusion changes on consecutive days in a larger population are lacking. In one study, MRI has been performed in three patients 2 days after onset of seizure and all patients still showed abnormalities in ADC.13,17,18 Changes on T2-weighted and FLAIR (fluid attenuated inversion recovery) images vary. In most patients no changes in signal intensity were visible within the first hours. In the experimental study about kainic acid induced complex partial status epilepticus in dogs, minimal changes on T2- and FLAIR images were visible in some brain areas after 12 h whereas the majority of changes was not visible until 48 h after the onset of the complex partial status epilepticus in contrast to diffusion images on which most of the examined regions showed significant changes after 6 h.13,18 The study of spontaneous epileptic brain diseases in dogs would be an interesting application for DWI. Even if imaging can usually not be performed within 30 min of onset, it is possible to image within 24 h after onset in most cases at which time changes on T2-weighted and FLAIR images might still be missing. In addition, DWI might be helpful in localizing the epileptic focus within the brain for presurgical planning as is done in human medicine.17 As published data about regional ADC values of normal canine brain parts are lacking, the aim of our study was to determine normal diffusion in selected brain areas, as revealed by ADC values in healthy dogs, to provide reference data for further studies.
Material and Methods The study was conducted prospectively from October to November 2011 and was approved by the local Hessian government (reference number: V54–19c2015(1)GI18/17
TABLE 1. Acquisition Parameters for the Transverse and Dorsal Diffusion-weighted Image
FOV Rectangular FOV Slice thickness TE TR Scan matrix Reconstruction matrix Voxel size (scan) (F × P × S)∗ Voxel size (recon) (F × P × S)∗ Scan time
150 mm 70 % 5.0 mm 136 ms 3535 ms 112 160
140 mm 65 % 5.0 mm 136 ms 2366 ms 112 160
1.34 × 2.10 × 5.00 mm
1.25 × 1.82 × 5.00 mm
0.94 × 0.92 × 5.00 mm
0.88 × 0.87 × 5.00 mm
FOV, field of view ∗ Frequency encoding direction × phase encoding direction × slice thickness.
Nr. 78/2011). Ten purpose-bred beagle dogs were used. The mean age was 2.4 ± 0.6 years (mean ± standard deviation (SD)) and the mean body weight was 9.5 ± 1.6 kg. Eight beagles were female, and two beagles were male. A general and neurological examination was performed prior to general anesthesia to exclude subclinical disease. In addition all dogs had a complete blood work done. Two venous catheters were placed, one in the right cephalic vein and one in the right saphenous vein. Dogs were preR medicated with diazepam (Diazepam-ratiopharm , Ratiopharm GmbH, Ulm, Germany, 0.5 mg/kg intravenously). General anesthesia was induced with propofol (2–4 mg/kg intravenously) until effect. After endotracheal intubation, anesthesia was maintained via 1.5%–2% isoflurane (Isoflo, R Albrecht , Aulendorf, Germany) and oxygen; all dogs were ventilated during MRI. Magnetic resonance imaging examination was performed using a 1.0 T (Philips Intera Gyroscan, Philips Healthcare, Hamburg, Germany) superconductive system and a sensitivity encoding (SENSE) coil (SENSE-flex M coil) consisting of two elliptical elements. The dogs were placed in sternal recumbency. The two elements of the coil were placed in a standardized way on the right and left sides of the head and were fixed with foam cushions. Dorsal and transverse T2-weighted images (time of echo, TE: 85 ms; time of repetition, TR: 4000 ms), transverse T2weighted FLAIR images (TE: 97.5 ms; TR: 3962 ms; time of inversion, TI: 2000 ms), and dorsal T1-weighted gradient echo images (TE: 6.9 ms; TR: 25 ms) pre- and postcontrast medium administration were acquired to exclude structural brain abnormalities. Diffusion-weighted images using a single shot echo planar imaging sequence (SSh-EPI) with a b value of b = 0 s/mm2 and b = 800 s/mm2 were acquired in a dorsal and transverse plane with diffusion gradients in all three planes (x-, y- and z-plane) before contrast medium administration. The acquisition parameters of the diffusion-weighted images are shown in Table 1. The
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FIG. 1. Transverse ADC maps showing the ROI placed around the caudate nucleus (A), the thalamus (B), the piriform lobe (C), and the hippocampus (D).
slices were orientated parallel (dorsal images) or perpendicular (transverse images) to the base of the skull with one slice (slice number 6) going through the thickest part of the caudate nucleus. After image acquisition, the computer automatically generated isometric images including the diffusion effects from all three-image planes. Using the integrated software, an ADC map of each acquired slice was generated. For the determination of regional signal intensity, regions of interest (ROIs) were manually drawn around the caudate nucleus, thalamus, piriform lobe, hippocampus, semioval center, and temporal cerebral cortex lateral to the semioval center (Figs. 1 and 2). The decision regarding a dorsal or transverse image for ROI placement was based on the subjective visibility of the structure on the respective image. The ROI was drawn on one representative slice; due to the slice thickness most structures were only visible on one slice. Images of the other sequences were available at time of ROI placement and served as reference for comparison of anatomic structures. The ROI for the caudate nucleus, thalamus, piriform lobe, and hippocampus were drawn on transverse images, whereas for the semioval center and temporal cerebral cortex, dorsal images were used (Figs. 1 and 2). The ROIs were drawn as large as possible avoiding the inclusion of other structures. The ROI drawings were repeated five times at different time points. The integrated software showed the distribution of ADC values in the ROI and the number of pixels showing the respective ADC, the minimum and maximum, as well the mean and
SD of ADC. The values of the calculated ADC maps are given in micro meter square per second (=10−6 mm2 /s). Statistical tests were selected and performed by statisticians. Statistical analysis was performed using the commercially available software (BMDP/Dynamic, Release 8.1).19 To evaluate the intraobserver variability, the mean variation was calculated by a multiway mixed-model analysis of variance with a random observer effect (program BMDP8V). The related coefficient of variation (%) was calculated by dividing this SD by the grand mean multiplied by 100. A two-way analysis of variance (ANOVA) with repeated measures was used to evaluate the effect of anatomical region and side (left versus right; program BMDP2V; ANOVA and covariance with repeated measures). As the interaction between the effects of region and side was statistically significant, a multiway mixed model analysis of variance (program BMDP8V) was used to determine the region-specific SD with respect to repeated measurements and to perform a region-specific side (left versus right) comparison. The Student—Newman–Keuls test was then used to compare the mean diffusion in the different regions with one another (pairwise comparison). The level of significance was P < 0.05 for all tests.
Results The caudate nucleus showed an ADC of 902.85 ± 193.88 µm2 /s (mean ± SD). The ADC of the thalamus was
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FIG. 2. Dorsal ADC maps (A + C) and T2 FFE images (B + D) showing the ROI placed around the semioval center (A) and the cerebral cortex (C). On the transverse T2 FFE images, the horizontal green lines show which area is covered by the ADC map, the vertical green line shows the medial border of the ROI on the respective ADC maps.
807.82 ± 128.41 µm2 /s. The piriform lobe had an ADC of 915.44 ± 159.84 µm2 /s. The hippocampus had an ADC of 1044.29 ± 165.21 µm2 /s. The ADC of the semioval center was 721.39 ± 126.28 µm2 /s. The temporal cerebral cortex showed an ADC of 843.15 ± 98.24 µm2 /s. Table 2 gives an overview of the ADC values, including minima, maxima for the right and left cerebral hemisphere individually, and the mean value for both cerebral hemispheres. With the exception of the hippocampus, there was slightly higher ADC measurable in the regions of the left cerebral hemisphere (Table 3). The mean intraobserver variability for all ROIs was 2.0%, the greatest degree of variation occurred in the caudate nucleus with a mean variation between ROIs of 3.3%, and the least variation occurred in the hippocampus with 1.2%. Applying the Student–Newman–Keuls test, a significant difference (P < 0.01) in ADC was found for the hippocampus compared to all other regions, as well as for the semioval center compared to all other regions. In addition, significant differences were found for the thalamus compared to the caudate nucleus and the piriform lobe. The twoway ANOVA with repeated measures showed a global sig-
nificant difference in ADC between the different regions (P < 0.0001). A significant difference was also found for the caudate nucleus (P = 0.0009), the thalamus (P = 0.018), and the piriform lobe (P = 0.0143) when comparing the right and left sides (Table 2).
Discussion In this study, we present the diffusion characteristics in the brain of healthy beagle dogs. All dogs were less than 3 years of age. We decided to use this age range of dogs because congenital diseases should have already become clinically apparent and the risk for age-related degenerative or neoplastic diseases was expected to be low. Subclinical disease was excluded by performing a complete general, neurological and hematological examination before the study, as well as obtaining additional MRI sequences (T2-weighted, T2-weighted FLAIR, T2 fast field echo, and T1-weighted images pre- and postcontrast medium administration) to rule out central nervous system changes. Further examination of cerebrospinal fluid would have been ideal, but was not done during this study.
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TABLE 2. ADC Values Given in µm2 /s (= 10−6 mm2 /s) of the Different Brain Regions Listed by Side. Significant Differences were Found for the Hippocampus and the Semioval Center Compared to all Other Regions, as well as for the Thalamus Compared to the Caudate Nucleus and the Piriform Lobe
Side Nucleus caudatus†
Right Left Right Left Right Left Right Left Right Left Right Left
Thalamus† Lobus piriformis† Hippocampus Semioval center Cortex cerebri
Mean ± SD∗ (µm2 /s)
Min. (µm2 /s)
Max. (µm2 /s)
± ± ± ± ± ± ± ± ± ± ± ±
751.7 864.4 741.7 794.9 806.0 898.0 902.4 919.5 597.0 609.5 738.5 809.0
1089.5 1125.0 833.2 874.8 962.5 1008.3 1236.3 1270.8 808.9 851.8 960.6 962.6
843.3 962.4 792.2 823.4 895.0 935.9 1052.9 1035.7 717.6 725.2 820.2 857.1
94.3 103.2 31.0 30.1 50.6 37.8 109.7 109.0 73.7 83.0 71.5 63.4
Mean ± SD∗ (µm2 /s) Right and left cerebral hemisphere combined 902.85 ± 193.88 807.82 ± 128.41 915 ± 159.84 1044.29 ± 165.21 721.39 ± 126.28 843.15 ± 98.24
Max., maximum ADC; Min., minimum ADC. ∗ SD. † Significant differences between ADC values of the right and left side. TABLE 3. Mean ADC Values Given in µm2 /s (= 10−6 mm2 /s) of the Different Brain Regions Listed by Side and Dog Brain region Dog 1∗ 2 3 4 5 6 7 8 9 10∗ Mean
Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left
1089.5 1125.0 812.4 900.0 808.8 867.9 751.7 887.1 790.9 864.4 801.5 1095.2 846.0 934.2 819.7 868.5 897.8 1069.4 814.7 1012.4
802.0 866.9 819.3 796.1 824.2 815.7 788.9 874.8 741.7 794.9 779.5 818.8 833.2 850.7 795.3 801.1 743.7 796.5 794.2 819.1
932.8 989.0 880.6 925.3 873.3 898.0 839.9 908.9 937.3 944.2 806.0 909.8 870.3 954.9 896.9 917.6 962.5 1008.3 950.3 903.6
1003,7 919.6 1130.4 1071.4 902.4 933.0 1236.3 992.7 1013.0 1270.8 1158.0 1166.6 937.7 1015.0 970.9 969.7 1153.6 985.4 1023.3 1032.5
738.8 818.5 727.1 717.1 798.7 723.1 765.0 851.8 808.9 728.8 755.2 786.3 597.0 705.7 720.5 726.3 651.0 609.5 613.5 585.1
738.5 853.0 752.0 809.0 960.6 888.7 827.5 875.1 787.6 878.0 822.6 820.8 935.5 850.5 851.7 906.9 802.4 962.6 814.0 726.3
855.0 928.7 853.6 869.8 861.3 854.4 868.2 898.4 846.6 913.5 853.8 932.9 836.6 885.2 842.5 865.0 868.5 905.3 835.0 846.5
Nc, nucleus caudatus; Th, thalmus; Lp, lobus piriformis; hip, hippocampus; Cs, centrum; semiovale; Cc, cortex cerebri. ∗ Male dogs.
Technical factors influencing DWI are magnetic field strength and b value. At 1.0 T, we could acquire diffusionweighted images of reasonable resolution.2 In our system, the chosen b value of b = 800 s/mm2 offered the best balance between signal for image reconstruction and measurable diffusion coefficient. The highest ADC was detected for the hippocampus, while the lowest ADC value was measured in the semioval center. Both differed significantly from all other regions. The ADC values of the other regions were intermediate.
Even though still under debate, the degree of myelination is considered a major limitation to isotropic diffusion.7,20,21 This is compatible with our results, as the semioval center, belonging to the white matter, showed the lowest signal intensity. The hippocampus is part of the archicortex and therefore belongs to the gray matter. It showed the highest signal intensity of all examined regions. The caudate nucleus, piriform lobe, and cerebral cortex are also part of the gray matter, and although their signal intensity did not differ
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significantly, the results were significantly different from those of the hippocampus. The difference in signal intensity might be the result of differences in neuronal density.21–24 We found a decreasing amount of diffusion (expressed by decreasing ADC ) with an increasing number of cell layers in the various cortical areas. Information on neuronal density is scarce. It has been shown that a great variability exists in cortical cytoarchitectonics amongst different species, but not within species. In addition, it has been shown that the density of neurons in the cortex in females is greater than in males.25 The influence of the cellular and subcellular composition of brain tissue on diffusion therefore remains unknown.26–28 Structural differences and differences in neuronal density could also be an explanation for the significant differences between the thalamus compared to the caudate nucleus, piriform lobe, and semioval center. The ADC value of the thalamus (807.82 ± 128.41 µm2 /s) is intermediate between the caudate nucleus (902.85 ± 193.88 µm2 /s), piriform lobe (915.44 ± 159.84 µm2 /s), and semioval center (721.39 ± 126.28 µm2 /s). This might reflect the histological structure of the thalamus, as it comprises different nuclei (gray matter), as well as fibers of white matter (laminae medullares thalami). This may result in some restriction of the diffusion of water molecules compared to the relatively unrestricted diffusion in gray matter structures such as the caudate nucleus and piriform lobe, while diffusion in the thalamus is less restricted compared to the highly restricted diffusion in pure white matter structures such as the semioval center.7,20,23,26,29 Overall, we discovered a difference between the ADC of the right versus left cerebral hemisphere, which was significant in the caudate nucleus, thalamus, and piriform lobe. With the exception of the hippocampus, the ADC was greater in the left hemisphere across all dogs. This might be explained by morphological differences between the right and left cerebral hemisphere. Asymmetries between the right and left cerebral hemisphere have been previously documented in dogs.30,31 If increased weight of one cerebral hemisphere is due to an increase in neuronal density, leading to a reduced space for diffusion, this could explain the overall decreased diffusion in the right cerebral hemisphere. However, this has not yet been proven. In human medicine, an increased anisotropy of the limbic system of the left cerebral hemisphere is described in right handedness.32 Studies dealing with paw preferences in dogs found a significant difference in hippocampal weight depending on pawedness. In female dogs, the weight of the hippocampus was significantly larger if the dogs were left-pawed, with the weight of the left hippocampus being larger than the right one. Also, the volume was significantly larger in left-pawed female dogs compared to right-pawed females.33
We found decreased diffusion in the right hippocampus, which suggests an increased neuronal density in the right hippocampus, and might be a sign of right paw preference in our dogs. We cannot exclude that the inclusion of parts of adjacent brain tissue occurred due to improper ROI placement, although this seems unlikely as the inclusion of adjacent brain tissue or part of the ventricular system would have led to an increase in ADC in most ROIs. Uneven signal detection by one element of the SENSE coil used cannot be excluded as cause for the differences in ADC values between the right and left cerebral hemisphere. Although it does not explain why the ADC in the hippocampus is reversed. We discovered minimal image distortion due to eddy current artifacts leading to shearing. This might have lead to inclusion of adjacent brain structures in our ROIs, which might differ between the right and left side. Though the distortion is only minimal and we chose to rather draw a smaller ROI not including the entire wanted structure but avoid the inclusion of unwanted structures. The ADC of our study should, theoretically, be comparable to values obtained with other systems. However, it has been shown that the ADC of gray and white matter varies 4%–9% between a 1.5 T and 3.0 T MRI system from the same vendor. Variations of up to 7% are possible using MRI systems from different vendors. When using the same MRI system, changing the coil can also lead to changes in the ADC of up to 8%. In this study, different persons were used for imaging; therefore, the variations might be due to individual differences in ADC between persons.34 However, we used the same MR system and the same coil for all patients. The aim of our study was to evaluate the normal distribution of diffusion in healthy mesaticephalic dogs. We found significant differences in ADC values between different brain regions, with the hippocampus showing the highest degree of diffusion and the semioval center showing the lowest. In human medicine, DWI may be helpful in differentiating underlying pathologies (ischemic, ictal, metabolic, or transient global amnesia) in hippocampal disorders.35 An increase of more than 2 SD in ADC values was found in the sclerotic hippocampi of patients suffering from epilepsy compared to normal volunteers.17 Similar results were achieved in an experimental study in dogs, showing an increase in ADC of more than 2 SD compared to baseline values.18 Our information may help in the earlier diagnosis of other diseases like epilepsy prior to vasogenic edema becoming apparent. Any change in ADC values of more than two SDs should raise suspicion of either necrosis or sclerosis of the respective brain area. None of our dogs showed values exceeding this range. Variations due to differences in MRI system, filed strength, or coil are also reported to be below this range. In human medicine, DWI
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is also used to identify the epileptic focus within the brain if surgery is planned.17 In conclusion, our results show that a comparison of ADC values should be done with caution as there seem to be significant physiological differences between ADC values in different brain regions and between the right and left cerebral hemispheres. Differences of less than two SDs should
especially be interpreted cautiously. Further research is to measure variations in ADC values using different scanners, different dog breeds, and different disease states. ACKNOWLEDGMENTS
The stastical anaylsis was performed by Mr Failing and Mr Schaubmar who are working in the Unit for Biomathematics and Data Processing.
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