title: Asymmetric dopaminergic degeneration and levodopa alter functional corticostriatal connectivity bilaterally in experimental parkinsonism.
abstract: 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.
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden. Electronic address: cyril.monnot@ki.se.
authors.forename: Cyril
authors.initials: C
authors.lastname: Monnot
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; Karolinska Experimental Research and Imaging Center, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Sahar
authors.initials: S
authors.lastname: Nikkhou-Aski
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; Karolinska Experimental Research and Imaging Center, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Damberg
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden. Electronic address: per.svenningsson@ki.se.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D056324:Diffusion Tensor Imaging / Q000379:methods; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology*; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism
chemical_list: D007980:Levodopa; D004298:Dopamine
keywords: 6-Hydroxydopamine; Animal model; Diffusion tensor imaging; Diffusion weighted MRI; Parkinson's disease; Resting-state functional MRI