Voxel-based morphometry, resting-state functional connectivity MRI and histological analysis for evaluating structural and functional changes in a rat model of Parkinson's disease

Introduction The neurotoxin 6-hydroxydopamine (6OHDA), when administered into the medial forebrain bundle (mfb) of rats, damages the dopaminergic nigrostriatal pathway. This models parkinsonian features such as reduced dopamine in the striatum1. The 6OHDA rat has been widely used as a test-bed for many therapeutic agents. The aim of this study was to further evaluate the 6OHDA rat in terms of structural and functional brain abnormalities in order to identify new biomarkers and targets for therapeutic interventions. Methods & Results Three weeks after unilateral 6OHDA lesioning of the mfb, male adult Sprague-Dawley rats (n=12-16 per group, full lesions were confirmed by apomorphine induced rotations) were imaged in vivo by structural (T2 weighted fast spin echo, resolution 0.25x0.125x0.5mm) and functional (gradient echo EPI TR=1s, resolution = 0.5x0.5x1mm) MRI. Structural images were analyzed using automated unbiased voxel-based morphometry2. Resulting statistical parametric maps revealed significant structural differences between the lesioned and sham groups. In particular, there was a reduction of grey matter volume (p<0.05, FDR corrected) in the ipsilateral (lesioned) hemisphere in the motor, sensorimotor, cingulate and temporal cortices. Grey matter volume loss was also present in the ipsilateral dorsal striatum and the substantia nigra (p<0.01, uncorrected). Functional images were analysed for resting-state connectivity using graph theoretical analysis and pattern recognition technique3. This demonstrated decreased connectivity between the ipsilateral motor and sensory cortex (including S1, S1 UlP and S2) with the contralateral parts of the brain. Dopaminergic neuronal loss and denervation was confirmed post-mortem by tyrosine hydroxylase immunohistochemistry in the nigrostriatal and cortical areas as highlighted by MRI analysis. Conclusions Studies to identify neuroprotective interventions in Parkinson’s disease have been hampered by the lack of clinically relevant animal models and the difficulty to detect brain pathology in vivo. This work demonstrates structural and functional brain changes on a topographic scale beyond the nigrostriatal tract in the 6OHDA rat by means of noninvasive and clinically relevant MRI protocols in conjunction with behaviour and histological methods. This highlights the beneficial use of the latest multiparametric MRI in animal models that allows the translational comparison between preclinical and clinical imaging and improves the predictive validity of the 6OHDA model. References 1. Duty et al, 2011, Br J Pharmacol, 2. Suzuki et al, 2013, Neuroimage, 3. Richiardi et al, 2012, Neuroimage.