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Longitudinal Anatomical and Diffusion MRI Evaluation in Rabbit External Capsules and Hippocampi after Cerebral Hemisphere Radiation Exposure

Purpose In the study, we used a linear accelerator as the source of radiation to establish an adult rabbit model for single-dose cerebral hemisphere exposure radiation-induced brain injury, and afterward, it longitudinally evaluated the changes in various brain compartments on a 1.5T clinical MR scanner by using T2 weighted imaging (T2WI) and diffusion tensor imaging (DTI) indices: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) mapping. It is hoped that this experimental model can be used to evaluate the neuro-toxic adverse effects of irradiation treatment. Materials and Methods Five male New Zealand rabbits of one year of age received irradiation of 30 Gy (collimations = 4 cm x 5 cm) to the right hemi-brain with a single highly collimated 6MV photon beam from a Varian CL21EX linear accelerator (Varian, Palo Alto, CA, USA) under anesthesia. Brain MRI examinations were performed before irradiation and at 1 to 48 week post-irradiation (totally 12 time points) on a 1.5T MR scanner (Sonata, Siemens, Erlangen, Germany) with double loop array coils. Whole brain coronal T2WI were obtained using TR/TE = 4330/114 ms, resolution = 0.19 x 0.39 x 1.5 mm, number of slices = 30. DTI data were acquired using a multi-slice, single-shot spin echo EPI sequence with TR/TE=2900/128 ms, resolution = 0.78 x 0.78 x 2 mm, number of slices = 12 (contiguously from the genu of the corpus callosum to the end of the cerebrum). They were obtained using 12 diffusion-encoding directions with b values changing from 0 to 2,000 s/mm. In data analysis, FA, MD, AD and RD maps were first calculated from DTI data using DSI studio (NTU, Taiwan) (Fig. 1A). Using imageJ (NIH, USA), ROIs were drawn manually on three consecutive slices of the DTI maps (both bilateral ECs and hippocampi) and the T2WI (only bilateral ECs). All the results were expressed as mean ± standard error (SE), and the ratios of right (injury) / left (control) were calculated for statistical analysis. Since the affected hippocampus was the only compartment which could be visually inspected as an increased signal intensity on T2WI (only occurred on the superior-lateral aspect, Fig. 2A), for a more appropriate specification of the change, we set the mean gray scale value of the control (left) side hippocampus as a threshold and then summarized the areas above the threshold of the three slices in each side of the hippocampus separately. All the results were calculated for statistical analysis. Paired t-test was used to detect statistical differences between the preand the post-irradiation time points. A p-value of <0.05 was considered to indicate statistical significance. After 48 week of MRI scans, rabbits were sacrificed for histopathological evaluation, and stained with hematoxylin and eosin (H&E) and Luxol fast blue (LFB). Results DTI indices: In EC, there was a continuing decrease followed by a gradual recovery in the FA R/L ratio during the follow-up time points, and the differences reached statistical significance at the 8 week (p-value = 0.0193) and the 12 week (p-value = 0.0373) post-irradiation. The gradual increase was followed by recovery in the RD and the MD R/L ratios and the AD R/L ratio showed a decrease at the 2 week and the 32 week post-irradiation (Fig. 1B). In hippocampus, the differences reached a statistical significance at the 20 week in the FA R/L ratio (p-value = 0.0405) and there was no clear trend in any DTI indices (Fig. 1C). T2WI: In hippocampus, the area above the threshold of the right hippocampus rapidly increased in the first two weeks and then reached a plateau (2 to 16 week), and this was followed by a gradual recovery after the 16 week post-irradiation. The differences reached a statistical significance at the 8 week (p-value = 0.0341) post-irradiation (Fig. 2B). In left hippocampus, the area above the threshold showed a continuing, gradual increase in the acute to early delayed phases followed by a rapid recovery after the 24 week post-irradiation (vertex at the 16 week). The differences reached a statistical significance at the 4 to 24 week (p-value < 0.05) post-irradiation (Fig. 2C). In EC, there was a continuing, gradual decrease at all the follow-up time points (Fig. 2D). Histopathology: One rabbit showed significant radiation-related alterations in right hemi-brains in both the H&E and LFB sections. Large areas of confluent coagulation necrosis and loss of the myelin sheath involving the right external capsule and hippocampus but not in the remaining right hemi-brain or non-irradiated left hemi-brain (Fig. 3).