The translational role of diffusion tensor image analysis in animal models of developmental pathologies

Abstract

Diffusion tensor magnetic resonance imaging (DTI) has proven itself a powerful technique for clinical investigation of the neurobiological targets and mechanisms underlying developmental pathologies. The success of DTI in clinical studies has demonstrated its great potential for understanding translational animal models of clinical disorders, and preclinical animal researchers are beginning to embrace this new technology to study developmental pathologies. In animal models, genetics can be effectively controlled, drugs consistently administered, subject compliance ensured, and image acquisition times dramatically increased to reduce between-subject variability and improve image quality. When pairing these strengths with the many positive attributes of DTI, such as the ability to investigate microstructural brain organization and connectivity, it becomes possible to delve deeper into the study of both normal and abnormal development. The purpose of this review is to provide new preclinical investigators with an introductory source of information about the analysis of data resulting from small animal DTI studies to facilitate the translation of these studies to clinical data. In addition to an in-depth review of translational analysis techniques, we present a number of relevant clinical and animal studies using DTI to investigate developmental insults in order to further illustrate techniques and to highlight where small animal DTI could potentially provide a wealth of translational data to inform clinical researchers.

Figure 1

An ROI-based examination of the volumetric differences in C57BL/6J mice on PND 42 following postnatal day seven hypoxic-ischemic brain injury [50]. Here, the authors demonstrate, in rostro-caudal order, manual ROI selections of the septal region (A) and hippocampus (B). The resolution of these images was 0.125mm³. The authors highlight other potential regions of interest, including the anterior commissure (ac), anterior part of the anterior commissure (aca), corpus callosum (cc), external capsule (ec), fornix (f), forceps major of the corpus callosum (fmj), and ventral hippocampal commissure (vhc). Results from this study demonstrated a significant impact of hypoxia-ischemia on the regions examined, with the extent of damage dependent upon the interval following the insult. While only volumetric differences were examined in this study, it would be possible to examine FA, MD, AD, and RD using similar methods.

Figure 2

Deformation Field Analysis of FA results from an investigation of mouse brain maturation over the postnatal period (PND 2-40) [70]. Difference maps (percent change) between young and old C57BL/6J mice, highlighting change in older brains compared to younger. Grey matter cortical and hippocampal regions show a drop in FA values over time (indicated by blue) whereas white matter structures, such as internal and external capsule, and the genu and splenium of the corpus callosum, show an increase in FA values (indicated by red). Comparing this normal trajectory of development to mouse models of developmental disorders could prove very informative.

Figure 3

In vivo 3D-fiber reconstruction of the adult rat brain taken from [78]. Tensors were calculated from 6 diffusion-weighted images at a resolution of 256×128×64μm. The tractography is presented atop a single representative 2D slice (non-typical slice orientations) to allow for anatomical association. The seed regions used for tractography included genu of corpus callosum (light blue), splenium of corpus callosum (pink), fimbria (blue), internal capsule (red), optic tract (green), striaterminalis (peach), and anterior commissure (yellow). This provides an excellent example of the usage of DTI in small animal subjects, and demonstrates its feasibility. Data collected from such studies can be used to quantitatively examine the various fiber tracks, which are likely targets of numerous developmental insults.

Figure 4

Mean Diffusivity (A and B) and Fractional Anisotropy (C and D) images of a postnatal day 14 Sprague Dawley rat pup brain. Following in vivo image collection shown in (A) and (C), the subject was perfused, decapitated, and whole head reimaged ex vivo shown in (B) and (D). In vivo scanning was accomplished under isoflurane anesthesia in our Bruker 9.4T MRI. A 3D RARE sequence was used with diffusion gradients applied in six non-collinear directions. Total scan time of approximately 2.5 hours, resulting in a resolution of 0.15×0.16×0.17mm. Ex vivo imaging was accomplished overnight via another RARE DTI scan protocol with 21 diffusion direction images at an isotropic voxel size of 0.12×0.12×0.12mm. The total scan time was approximately 15.5 hours. By comparing these two images, we can see both the greater resolution and SNR of the fixed brain images, which came at the cost of reduced translational relevancy and the sacrifice of a longitudinal study design.