MR Diffusion Histology and Micro-Tractography Reveal Mesoscale Features of the Human Cerebellum

After 140 years from the discovery of Golgi’s black reaction, the study of connectivity of the cerebellum remains a fascinating yet challenging task. Current histological techniques provide powerful methods for unravelling local axonal architecture, but the relatively low volume of data that can be acquired in a reasonable amount of time limits their application to small samples. State-of-the-art in vivo magnetic resonance imaging (MRI) methods, such as diffusion tractography techniques, can reveal trajectories of the major white matter pathways, but their correspondence with underlying anatomy is yet to be established. Hence, a significant gap exists between these two approaches as neither of them can adequately describe the three-dimensional complexity of fibre architecture at the level of the mesoscale (from a few millimetres to micrometres). In this study, we report the application of MR diffusion histology and micro-tractography methods to reveal the combined cytoarchitectural organisation and connectivity of the human cerebellum at a resolution of 100-μm (2 nl/voxel volume). Results show that the diffusion characteristics for each layer of the cerebellar cortex correctly reflect the known cellular composition and its architectural pattern. Micro-tractography also reveals details of the axonal connectivity of individual cerebellar folia and the intra-cortical organisation of the different cerebellar layers. The direct correspondence between MR diffusion histology and micro-tractography with immunohistochemistry indicates that these approaches have the potential to complement traditional histology techniques by providing a non-destructive, quantitative and three-dimensional description of the microstructural organisation of the healthy and pathological tissue

Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington's Disease

A variety of mouse models have been developed that express mutant huntingtin (mHTT) leading to aggregates and inclusions that model the molecular pathology observed in Huntington’s disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength) by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction) was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT) and HdhQ150 mice being present even at 15 weeks. Indeed, MRI indicated significant volumetric changes prior to the emergence of the “clinical horizon” of motor impairments at 36 weeks of age. A striatal decrease of 27% was observed over 94 weeks with cortex (12%) and hippocampus (21%) also indicating significant atrophy. A hypothesis-free analysis using tensor-based morphometry highlighted further regions undergoing atrophy by contrasting brain growth and regional neurodegeneration. Histology revealed the widespread presence of mHTT aggregates and cellular inclusions. However, there was little evidence of correlations between these outcome measures, potentially indicating that other factors are important in the causal cascade linking the molecular pathology to the emergence of behavioral impairments. In conclusion, the HdhQ150 mouse model replicates many aspects of the human condition, including an extended pre-manifest period prior to the emergence of motor impairments

A Comparison of Automated Anatomical-Behavioural Mapping Methods in a Rodent Model of Stroke

Neurological damage, due to conditions such as stroke, results in a complex pattern of structural changes and significant behavioural dysfunctions; the automated analysis of magnetic resonance imaging (MRI) and discovery of structural-behavioural correlates associated with these disorders remains challenging. Voxel lesion symptom mapping (VLSM) has been used to associate behaviour with lesion location in MRI, but this analysis requires the definition of lesion masks on each subject and does not exploit the rich structural information in the images. Tensor-based morphometry (TBM) has been used to perform voxel-wise structural analyses over the entire brain; however, a combination of lesion hyper-intensities and subtle structural remodelling away from the lesion might confound the interpretation of TBM. In this study, we compared and contrasted these techniques in a rodent model of stroke (n=58) to assess the efficacy of these techniques in a challenging pre-clinical application. The results from the automated techniques were compared using manually derived region-of-interest measures of the lesion, cortex, striatum, ventricle and hippocampus, and considered against model power calculations. The automated TBM techniques successfully detect both lesion and non-lesion effects, consistent with manual measurements. These techniques do not require manual segmentation to the same extent as VLSM and should be considered part of the toolkit for the unbiased analysis of pre-clinical imaging-based studies