Levodopa has been the mainstay of symptomatic therapy for Parkinson's disease (PD) for the last five decades. However, it is associated with the development of motor fluctuations and dyskinesia, in particular after several years of treatment. The aim of this study was to shed light on the acute brain functional reorganization in response to a single levodopa dose. Functional magnetic resonance imaging (fMRI) was performed after an overnight withdrawal of dopaminergic treatment and 1 h after a single dose of 250 mg levodopa in a group of 24 PD patients. Eigenvector centrality was calculated in both treatment states using resting-state fMRI. This offers a new data-driven and parameter-free approach, similar to Google's PageRank algorithm, revealing brain connectivity alterations due to the effect of levodopa treatment. In all PD patients, levodopa treatment led to an improvement of clinical symptoms as measured with the Unified Parkinson's Disease Rating Scale motor score (UPDRS-III). This therapeutic effect was accompanied with a major connectivity increase between cerebellar brain regions and subcortical areas of the motor system such as the thalamus, putamen, globus pallidus, and brainstem. The degree of interconnectedness of cerebellar regions correlated with the improvement of clinical symptoms due to the administration of levodopa. We observed significant functional cerebellar connectivity reorganization immediately after a single levodopa dose in PD patients. Enhanced general connectivity (eigenvector centrality) was associated with better motor performance as assessed by UPDRS-III score. This underlines the importance of considering cerebellar networks as therapeutic targets in PD.

Clinic for Cognitive Neurology University Hospital Leipzig Leipzig Germany

Department of Neurology Center for interventional therapy of movement disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Radiology Na Homolce Hospital Prague Czech Republic

Max Planck Institute for Human Cognitive and Brain Sciences Leipzig Germany

Zobrazit více v PubMed

Chrischilles EA, Rubenstein LM, Voelker MD, Wallace RB, Rodnitzky RL. The health burdens of Parkinson’s disease. Mov Disord. 1998;13(3):406–413. doi: 10.1002/mds.870130306. PubMed DOI

Huse DM, Schulman K, Orsini L, Castelli-Haley J, Kennedy S, Lenhart G. Burden of illness in Parkinson’s disease. Mov Disord. 2005;20(11):1449–1454. doi: 10.1002/mds.20609. PubMed DOI

Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, Marshall FJ, Ravina BM, Schifitto G, Siderowf A, Tanner CM. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384–386. doi: 10.1212/01.wnl.0000247740.47667.03. PubMed DOI

Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinsonism. N Engl J Med. 1967;276(7):374–379. doi: 10.1056/NEJM196702162760703. PubMed DOI

Olanow CW, Agid Y, Mizuno Y, Albanese A, Bonuccelli U, Damier P, et al. Levodopa in the treatment of Parkinson’s disease: current controversies. Mov Disord. 2004;19(9):997–1005. doi: 10.1002/mds.20243. PubMed DOI

Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord. 2001;16(3):448–458. doi: 10.1002/mds.1090. PubMed DOI

Obeso JA, Olanow CW, Nutt JG. Levodopa motor complications in Parkinson’s disease. New York City: Elsevier; 2000. PubMed

Zhuang X, Mazzoni P, Kang UJ. The role of neuroplasticity in dopaminergic therapy for Parkinson disease. Nat Rev Neurol. 2013;9(5):248–256. doi: 10.1038/nrneurol.2013.57. PubMed DOI

Olanow CW, Obeso JA. Levodopa toxicity and Parkinson disease: still a need for equipoise. Neurology. 2011;77(15):1416–1417. doi: 10.1212/WNL.0b013e318232ac0a. PubMed DOI

Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol. 2011;69(2):269–281. doi: 10.1002/ana.22361. PubMed DOI

Nutt JG. Pharmacokinetics and pharmacodynamics of levodopa. Mov Disord. 2008;23(Suppl 3):S580–S584. doi: 10.1002/mds.22037. PubMed DOI

Whitfield AC, Moore BT, Daniels RN. Classics in chemical neuroscience: levodopa. ACS Chem Neurosci. 2014;5(12):1192–1197. doi: 10.1021/cn5001759. PubMed DOI

Tedroff J, Pedersen M, Aquilonius S, Hartvig P, Jacobsson G, Långström B. Levodopa-induced changes in synaptic dopamine in patients with Parkinson’s disease as measured by [11C] raclopride displacement and PET. Neurology. 1996;46(5):1430–1436. doi: 10.1212/WNL.46.5.1430. PubMed DOI

Lang AE, Obeso JA. Challenges in Parkinson’s disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol. 2004;3(5):309–316. doi: 10.1016/S1474-4422(04)00740-9. PubMed DOI

Prodoehl J, Burciu RG, Vaillancourt DE. Resting state functional magnetic resonance imaging in Parkinson’s disease. Curr Neurol Neurosci Rep. 2014;14(6):448. doi: 10.1007/s11910-014-0448-6. PubMed DOI

Tahmasian M, Eickhoff SB, Giehl K, Schwartz F, Herz DM, Drzezga A, van Eimeren T, Laird AR, Fox PT, Khazaie H, Zarei M, Eggers C, Eickhoff CR. Resting-state functional reorganization in Parkinson’s disease: an activation likelihood estimation meta-analysis. Cortex. 2017;92:119–138. doi: 10.1016/j.cortex.2017.03.016. PubMed DOI PMC

Tahmasian M, Bettray LM, van Eimeren T, Drzezga A, Timmermann L, Eickhoff CR, Eickhoff SB, Eggers C. A systematic review on the applications of resting-state fMRI in Parkinson’s disease: does dopamine replacement therapy play a role? Cortex. 2015;73:80–105. doi: 10.1016/j.cortex.2015.08.005. PubMed DOI

Warren JD, Rohrer JD, Schott JM, Fox NC, Hardy J, Rossor MN. Molecular nexopathies: a new paradigm of neurodegenerative disease. Trends Neurosci. 2013;36(10):561–569. doi: 10.1016/j.tins.2013.06.007. PubMed DOI PMC

Cerasa A, Novellino F, Quattrone A. Connectivity changes in Parkinson’s disease. Curr Neurol Neurosci Rep. 2016;16(10):91. doi: 10.1007/s11910-016-0687-9. PubMed DOI

Lohmann G, Margulies DS, Horstmann A, Pleger B, Lepsien J, Goldhahn D, Schloegl H, Stumvoll M, Villringer A, Turner R. Eigenvector centrality mapping for analyzing connectivity patterns in fMRI data of the human brain. PLoS One. 2010;5(4):e10232. doi: 10.1371/journal.pone.0010232. PubMed DOI PMC

Levy G. The relationship of Parkinson disease with aging. Arch Neurol. 2007;64(9):1242–1246. doi: 10.1001/archneur.64.9.1242. PubMed DOI

Durso R, Isaac K, Perry L, Saint-Hilaire M, Feldman RG. Age influences magnitude but not duration of response to levodopa. J Neurol Neurosurg Psychiatry. 1993;56(1):65–68. doi: 10.1136/jnnp.56.1.65. PubMed DOI PMC

Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord. 2010;25(15):2649–2653. doi: 10.1002/mds.23429. PubMed DOI

Ashburner J, Friston KJ. Unified segmentation. NeuroImage. 2005;26(3):839–851. doi: 10.1016/j.neuroimage.2005.02.018. PubMed DOI

Lohmann G, Muller K, Bosch V, Mentzel H, Hessler S, Chen L, et al. LIPSIA--a new software system for the evaluation of functional magnetic resonance images of the human brain. Comput Med Imaging Graph. 2001;25(6):449–457. doi: 10.1016/S0895-6111(01)00008-8. PubMed DOI

Frobenius G. On matrices from non negative elements. Sitzber K Preuss Aka. 1912:456–77.

Perron O. On the theory of matrices. Math Ann. 1907;64:248–263. doi: 10.1007/BF01449896. DOI

Eklund A, Nichols TE, Knutsson H. Cluster failure: why fMRI inferences for spatial extent have inflated false-positive rates. Proc Natl Acad Sci U S A. 2016;113(28):7900–7905. doi: 10.1073/pnas.1602413113. PubMed DOI PMC

Smith SM, Nichols TE. Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. NeuroImage. 2009;44(1):83–98. doi: 10.1016/j.neuroimage.2008.03.061. PubMed DOI

Helmich RC. The cerebral basis of Parkinsonian tremor: a network perspective. Mov Disord. 2018;33(2):219–231. doi: 10.1002/mds.27224. PubMed DOI

Jech R, Mueller K, Schroeter ML, Ruzicka E. Levodopa increases functional connectivity in the cerebellum and brainstem in Parkinson’s disease. Brain. 2013;136(Pt 7):e234. doi: 10.1093/brain/awt015. PubMed DOI

Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. NeuroImage. 2012;59(3):2142–2154. doi: 10.1016/j.neuroimage.2011.10.018. PubMed DOI PMC

Wu T, Hallett M. The cerebellum in Parkinson’s disease. Brain. 2013;136(Pt 3):696–709. doi: 10.1093/brain/aws360. PubMed DOI PMC

Bostan AC, Dum RP, Strick PL. The basal ganglia communicate with the cerebellum. Proc Natl Acad Sci U S A. 2010;107(18):8452–8456. doi: 10.1073/pnas.1000496107. PubMed DOI PMC

Hoshi E, Tremblay L, Feger J, Carras PL, Strick PL. The cerebellum communicates with the basal ganglia. Nat Neurosci. 2005;8(11):1491–1493. doi: 10.1038/nn1544. PubMed DOI

Kelly C, de Zubicaray G, Di Martino A, Copland DA, Reiss PT, Klein DF, et al. L-dopa modulates functional connectivity in striatal cognitive and motor networks: a double-blind placebo-controlled study. J Neurosci. 2009;29(22):7364–7378. doi: 10.1523/JNEUROSCI.0810-09.2009. PubMed DOI PMC

Helmich RC, Derikx LC, Bakker M, Scheeringa R, Bloem BR, Toni I. Spatial remapping of cortico-striatal connectivity in Parkinson’s disease. Cereb Cortex. 2010;20(5):1175–1186. doi: 10.1093/cercor/bhp178. PubMed DOI

Wu T, Long X, Zang Y, Wang L, Hallett M, Li K, Chan P. Regional homogeneity changes in patients with Parkinson’s disease. Hum Brain Mapp. 2009;30(5):1502–1510. doi: 10.1002/hbm.20622. PubMed DOI PMC

Yang H, Zhou XJ, Zhang MM, Zheng XN, Zhao YL, Wang J. Changes in spontaneous brain activity in early Parkinson’s disease. Neurosci Lett. 2013;549:24–28. doi: 10.1016/j.neulet.2013.05.080. PubMed DOI

Simioni AC, Dagher A, Fellows LK. Compensatory striatal-cerebellar connectivity in mild-moderate Parkinson’s disease. Neuroimage Clin. 2016;10:54–62. doi: 10.1016/j.nicl.2015.11.005. PubMed DOI PMC

Hacker CD, Perlmutter JS, Criswell SR, Ances BM, Snyder AZ. Resting state functional connectivity of the striatum in Parkinson’s disease. Brain. 2012;135(Pt 12):3699–3711. doi: 10.1093/brain/aws281. PubMed DOI PMC

Zaidel A, Arkadir D, Israel Z, Bergman H. Akineto-rigid vs. tremor syndromes in Parkinsonism. Curr Opin Neurol. 2009;22(4):387–393. doi: 10.1097/WCO.0b013e32832d9d67. PubMed DOI

Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79(4):368–376. doi: 10.1136/jnnp.2007.131045. PubMed DOI

Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197–211. doi: 10.1016/S0197-4580(02)00065-9. PubMed DOI

Vaillancourt D, Spraker M, Prodoehl J, Abraham I, Corcos D, Zhou X, et al. High-resolution diffusion tensor imaging in the substantia nigra of de novo Parkinson disease. Neurology. 2009;72(16):1378–1384. doi: 10.1212/01.wnl.0000340982.01727.6e. PubMed DOI PMC

Guan X, Zeng Q, Guo T, Wang J, Xuan M, Gu Q, Wang T. Disrupted functional connectivity of basal ganglia across tremor-dominant and akinetic/rigid-dominant Parkinson’s disease. Front Aging Neurosci. 2017;9:360. doi: 10.3389/fnagi.2017.00360. PubMed DOI PMC

Dirkx MF, den Ouden HE, Aarts E, Timmer MH, Bloem BR, Toni I, et al. Dopamine controls Parkinson’s tremor by inhibiting the cerebellar thalamus. Brain. 2017;140(3):721–734. PubMed

Esposito F, Tessitore A, Giordano A, De Micco R, Paccone A, Conforti R, et al. Rhythm-specific modulation of the sensorimotor network in drug-naive patients with Parkinson’s disease by levodopa. Brain. 2013;136(Pt 3):710–725. doi: 10.1093/brain/awt007. PubMed DOI

Wu T, Wang L, Chen Y, Zhao C, Li K, Chan P. Changes of functional connectivity of the motor network in the resting state in Parkinson’s disease. Neurosci Lett. 2009;460(1):6–10. doi: 10.1016/j.neulet.2009.05.046. PubMed DOI

Brichta L, Greengard P, Flajolet M. Advances in the pharmacological treatment of Parkinson’s disease: targeting neurotransmitter systems. Trends Neurosci. 2013;36(9):543–554. doi: 10.1016/j.tins.2013.06.003. PubMed DOI

Bostan AC, Dum RP, Strick PL. Cerebellar networks with the cerebral cortex and basal ganglia. Trends Cogn Sci. 2013;17(5):241–254. doi: 10.1016/j.tics.2013.03.003. PubMed DOI PMC

Buckner RL. The cerebellum and cognitive function: 25 years of insight from anatomy and neuroimaging. Neuron. 2013;80(3):807–815. doi: 10.1016/j.neuron.2013.10.044. PubMed DOI

Pagano G, Ferrara N, Brooks DJ, Pavese N. Age at onset and Parkinson disease phenotype. Neurology. 2016;86(15):1400–1407. doi: 10.1212/WNL.0000000000002461. PubMed DOI PMC

Symptom-severity-related brain connectivity alterations in functional movement disorders