Asymmetric dopaminergic degeneration and levodopa alter functional corticostriatal connectivity bilaterally in experimental parkinsonism.

Asymmetric dopamine loss is commonly found in early Parkinson's disease (PD), but its effects on functional networks have been difficult to delineate in PD patients because of variations in age, disease duration and therapy. Here we used unilateral 6-hydroxydopamine-lesioned (6-OHDA) rats and controls and treated them with a single intraperitoneal injection of levodopa (L-DOPA) before performing diffusion weighted MRI and resting state functional MRI (rs-fMRI). In accordance with a neurodegeneration of the nigrostriatal dopaminergic pathway, diffusion tensor imaging showed increased radial diffusivity and decreased fractional anisotropy in the lesioned substantia nigra. Likewise a deterministic connectometry approach showed increase of isotropic diffusion values in the medial forebrain bundle. rs-fMRI showed reduced interhemispheric functional connectivity (FC) between the intact and the 6-OHDA lesioned caudate-putamen. Unexpectedly, there was an increased FC between the 6-OHDA lesioned caudate-putamen and sensorimotor cortices of both hemispheres. L-DOPA reversed the FC changes between the dopamine denervated caudate-putamen and the sensorimotor cortices, but not the reduced interhemispheric FC between caudate-putamina. Similarly, L-DOPA induced c-fos expression in both sensorimotor cortices, but only in the dopamine-depleted caudate-putamen. Taken together, these data suggest that asymmetric degeneration of the nigrostriatal dopamine pathway results in functional asynchrony between the intact and 6-OHDA-lesioned caudate-putamen and increased interhemispheric synchrony between sensorimotor cortices. The results also indicate that the initial effect of L-DOPA is to restore functional corticostriatal connectivity rather than synchronize caudate-putamina.

Default mode network, motor network, dorsal and ventral basal ganglia networks in the rat brain: comparison to human networks using resting state-fMRI.

Rodent models are developed to enhance understanding of the underlying biology of different brain disorders. However, before interpreting findings from animal models in a translational aspect to understand human disease, a fundamental step is to first have knowledge of similarities and differences of the biological systems studied. In this study, we analyzed and verified four known networks termed: default mode network, motor network, dorsal basal ganglia network, and ventral basal ganglia network using resting state functional MRI (rsfMRI) in humans and rats. Our work supports the notion that humans and rats have common robust resting state brain networks and that rsfMRI can be used as a translational tool when validating animal models of brain disorders. In the future, rsfMRI may be used, in addition to short-term interventions, to characterize longitudinal effects on functional brain networks after long-term intervention in humans and rats.