The effects of dopaminergic therapy for Parkinson's disease (PD) on the brain functional architecture are still unclear. We investigated this topic in 31 PD patients (disease duration: 11.2 ± (SD) 3.6 years) who underwent clinical and MRI assessments under chronic dopaminergic treatment (duration: 8.3 ± (SD) 4.4 years) and after its withdrawal. Thirty healthy controls were also included. Functional and morphological changes were studied, respectively, with eigenvector centrality mapping and seed-based connectivity, and voxel-based morphometry. Patients off medication, compared to controls, showed increased connectivity in cortical sensorimotor areas extending to the cerebello-thalamo-cortical pathway and parietal and frontal brain structures. Dopaminergic therapy normalized this increased connectivity. Notably, patients showed decreased interconnectedness in the medicated compared to the unmedicated condition, encompassing putamen, precuneus, supplementary motor and sensorimotor areas bilaterally. Similarly, lower connectivity was found comparing medicated patients to controls, overlapping with the within-group comparison in the putamen. Seed-based analyses revealed that dopaminergic therapy reduced connectivity in motor and default mode networks. Lower connectivity in the putamen correlated with longer disease duration, medication dose, and motor symptom improvement. Notably, atrophy and connectivity changes were topographically dissociated. After chronic treatment, dopaminergic therapy decreases connectivity of key motor and default mode network structures that are abnormally elevated in PD off condition.

Clinic for Cognitive Neurology University Clinic Leipzig Germany

Department of Neurology Charles University Prague 1st Faculty of Medicine Prague Czech Republic

Department of Radiology Na Homolce Hospital Prague Czech Republic

FTLD Consortium Ulm Germany

Max Planck Institute for Human Cognitive and Brain Sciences Leipzig Germany

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de Lau LML, Breteler MMB. Epidemiology of Parkinson’s disease. The Lancet Neurology. 2006;5:525–535. doi: 10.1016/s1474-4422(06)70471-9. PubMed DOI

Schapira AH. Recent developments in biomarkers in Parkinson disease. Curr Opin Neurol. 2013;26:395–400. doi: 10.1097/WCO.0b013e3283633741. PubMed DOI PMC

Braak H, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging. 2003;24:197–211. doi: 10.1016/S0197-4580(02)00065-9. PubMed DOI

Warren JD, Rohrer JD, Hardy J. Disintegrating brain networks: from syndromes to molecular nexopathies. Neuron. 2012;73:1060–1062. doi: 10.1016/j.neuron.2012.03.006. PubMed DOI PMC

Warren JD, et al. Molecular nexopathies: a new paradigm of neurodegenerative disease. Trends Neurosci. 2013;36:561–569. doi: 10.1016/j.tins.2013.06.007. PubMed DOI PMC

LeWitt PA. Levodopa for the treatment of Parkinson’s disease. The New England Journal of Medicine. 2008;359:2468–2476. doi: 10.1056/NEJMct0800326. PubMed DOI

Aquino CC, Fox SH. Clinical spectrum of levodopa-induced complications. Mov Disord. 2015;30:80–89. doi: 10.1002/mds.26125. PubMed DOI

Vijayakumar D, Jankovic JD-I. Dyskinesia, Part 1: Treatment of Levodopa-Induced Dyskinesia. Drugs. 2016;76:759–777. doi: 10.1007/s40265-016-0566-3. PubMed DOI

Tahmasian M, et al. 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

Berman BD, et al. Levodopa modulates small-world architecture of functional brain networks in Parkinson’s disease. Mov Disord. 2016;31:1676–1684. doi: 10.1002/mds.26713. PubMed DOI PMC

Gao LL, Zhang JR, Chan P, Wu T. Levodopa Effect on Basal Ganglia Motor Circuit in Parkinson’s Disease. CNS Neurosci Ther. 2017;23:76–86. doi: 10.1111/cns.12634. PubMed DOI PMC

Kwak Y, et al. Altered resting state cortico-striatal connectivity in mild to moderate stage Parkinson’s disease. Front Syst Neurosci. 2010;4:143. doi: 10.3389/fnsys.2010.00143. PubMed DOI PMC

Kwak Y, et al. L-DOPA changes spontaneous low-frequency BOLD signal oscillations in Parkinson’s disease: a resting state fMRI study. Front Syst Neurosci. 2012;6:52. doi: 10.3389/fnsys.2012.00052. PubMed DOI PMC

Szewczyk-Krolikowski K, et al. Functional connectivity in the basal ganglia network differentiates PD patients from controls. Neurology. 2014;83:208–214. doi: 10.1212/WNL.0000000000000592. PubMed DOI PMC

Vo A, et al. Parkinson’s disease-related network topographies characterized with resting state functional MRI. Hum Brain Mapp. 2017;38:617–630. doi: 10.1002/hbm.23260. PubMed DOI PMC

Wu T, et al. Regional homogeneity changes in patients with Parkinson’s disease. Hum Brain Mapp. 2009;30:1502–1510. doi: 10.1002/hbm.20622. PubMed DOI PMC

Wu T, et al. Changes of functional connectivity of the motor network in the resting state in Parkinson’s disease. Neurosci Lett. 2009;460:6–10. doi: 10.1016/j.neulet.2009.05.046. PubMed DOI

Esposito F, et al. Rhythm-specific modulation of the sensorimotor network in drug-naive patients with Parkinson’s disease by levodopa. Brain. 2013;136:710–725. doi: 10.1093/brain/awt007. PubMed DOI

Wu T, et al. Basal ganglia circuits changes in Parkinson’s disease patients. Neurosci Lett. 2012;524:55–59. doi: 10.1016/j.neulet.2012.07.012. PubMed DOI PMC

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

Lohmann G, et al. Eigenvector centrality mapping for analyzing connectivity patterns in fMRI data of the human brain. PLoS One. 2010;5:e10232. doi: 10.1371/journal.pone.0010232. PubMed DOI PMC

Brin S, Page L. Reprint of: The anatomy of large-scale hypertextual web search engine. Computer networks. 2012;58:3825–3833. doi: 10.1016/j.comnet.2012.10.007. DOI

Zappia M, et al. Long-Duration Response to Levodopa Influences the Pharmacodynamics of Short-Duration Response in Parkinson’s Disease. Annals of Neurology. 1997;42:245–248. doi: 10.1002/ana.410420217. PubMed DOI

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

Reynolds JNJ, Wickens JR. Dopamine-dependent plasticity of corticostriatal synapses. Neural Networks. 2002;15:507–521. doi: 10.1016/S0893-6080(02)00045-X. PubMed DOI

Akram H, et al. l-Dopa responsiveness is associated with distinctive connectivity patterns in advanced Parkinson’s disease. Mov Disord. 2017;32:874–883. doi: 10.1002/mds.27017. PubMed DOI PMC

Wink AM, de Munck JC, van der Werf YD, van den Heuvel OA, Barkhof F. Fast eigenvector centrality mapping of voxel-wise connectivity in functional magnetic resonance imaging: implementation, validation, and interpretation. Brain Connect. 2012;2:265–274. doi: 10.1089/brain.2012.0087. PubMed DOI

Yang W, et al. Altered Resting-State Functional Connectivity of the Striatum in Parkinson’s Disease after Levodopa Administration. PLoS One. 2016;11:e0161935. doi: 10.1371/journal.pone.0161935. PubMed DOI PMC

Lewis MM, et al. Differential involvement of striato- and cerebello-thalamo-cortical pathways in tremor- and akinetic/rigid-predominant Parkinson’s disease. Neuroscience. 2011;177:230–239. doi: 10.1016/j.neuroscience.2010.12.060. PubMed DOI PMC

Sen S, Kawaguchi A, Truong Y, Lewis MM, Huang X. Dynamic changes in cerebello-thalamo-cortical motor circuitry during progression of Parkinson’s disease. Neuroscience. 2010;166:712–719. doi: 10.1016/j.neuroscience.2009.12.036. PubMed DOI PMC

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

Zhang D, Liu X, Chen J, Liu B, Wang J. Widespread increase of functional connectivity in Parkinson’s disease with tremor: a resting-state FMRI study. Front Aging Neurosci. 2015;7:6. doi: 10.3389/fnagi.2015.00006. PubMed DOI PMC

Tessitore A, et al. Default-mode network connectivity in cognitively unimpaired patients with Parkinson disease. Neurology. 2012;79:2226–2232. doi: 10.1212/WNL.0b013e31827689d6. PubMed DOI

Zou Q-H, et al. An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: Fractional ALFF. Journal of neuroscience methods. 2008;172:137–141. doi: 10.1016/j.jneumeth.2008.04.012. PubMed DOI PMC

Tahmasian M, et al. 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

Costa RM, et al. Rapid alterations in corticostriatal ensemble coordination during acute dopamine-dependent motor dysfunction. Neuron. 2006;52:359–369. doi: 10.1016/j.neuron.2006.07.030. PubMed DOI

Wang M, et al. Altered neuronal activity in the primary motor cortex and globus pallidus after dopamine depletion in rats. J Neurol Sci. 2015;348:231–240. doi: 10.1016/j.jns.2014.12.014. PubMed DOI

Eusebio A, et al. Resonance in subthalamo-cortical circuits in Parkinson’s disease. Brain. 2009;132:2139–2150. doi: 10.1093/brain/awp079. PubMed DOI PMC

Appel-Cresswell S, de la Fuente-Fernandez R, Galley S, McKeown MJ. Imaging of compensatory mechanisms in Parkinson’s disease. Curr Opin Neurol. 2010;23:407–412. doi: 10.1097/WCO.0b013e32833b6019. PubMed DOI

Lou Y, et al. Altered brain network centrality in depressed Parkinson’s disease patients. Mov Disord. 2015;30:1777–1784. doi: 10.1002/mds.26321. PubMed DOI

Jung Kang U, et al. Activity enhances dopaminergic long-duration response in Parkinson disease. Neurology. 2012;78:1146–1149. doi: 10.1212/WNL.0b013e31824f8056. PubMed DOI PMC

Kelly C, et al. L-dopa modulates functional connectivity in striatal cognitive and motor networks: a double-blind placebo-controlled study. J Neurosci. 2009;29:7364–7378. doi: 10.1523/JNEUROSCI.0810-09.2009. PubMed DOI PMC

Saeed U, et al. Imaging biomarkers in Parkinson’s disease and Parkinsonian syndromes: current and emerging concepts. Transl Neurodegener. 2017;6:8. doi: 10.1186/s40035-017-0076-6. PubMed DOI PMC

Logothetis NK, Wandell BA. Interpreting the BOLD Signal. Annual Review of Physiology. 2004;66:735–769. doi: 10.1146/annurev.physiol.66.082602.092845. PubMed DOI

Girouard H, Iadecola C. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. Journal of applied physiology. 2006;100:328–335. doi: 10.1152/japplphysiol.00966.2005. PubMed DOI

Phillips AA, Chan FH, Zheng MMZ, Krassioukov AV, Ainslie PN. Neurovascular coupling in humans: Physiology, methodological advances and clinical implications. Journal of Cerebral Blood Flow & Metabolism. 2016;36:647–664. doi: 10.1177/0271678X15617954. PubMed DOI PMC

Rosengarten B, et al. Neurovascular coupling in Parkinson’s disease patients: effects of dementia and acetylcholinesterase inhibitor treatment. Journal of Alzheimer’s Disease. 2010;22:415–421. doi: 10.3233/JAD-2010-101140. PubMed DOI

Krainik A, et al. Levodopa does not change cerebral vasoreactivity in Parkinson’s disease. Movement Disorders. 2013;28:469–475. doi: 10.1002/mds.25267. PubMed DOI

Hanby MF, Panerai RB, Robinson TG, Haunton VJ. Is cerebral vasomotor reactivity impaired in Parkinson disease? Clinical Autonomic Research. 2017;27:107–111. doi: 10.1007/s10286-017-0406-x. PubMed DOI

Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. Journal of Neurology, Neurosurgery & Psychiatry. 1992;55:181. doi: 10.1136/jnnp.55.3.181. PubMed DOI PMC

Tomlinson CL, et al. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord. 2010;25:2649–2653. doi: 10.1002/mds.23429. PubMed DOI

Kopecek M, et al. Montreal cognitive assessment (MoCA): Normative data for old and very old Czech adults. Appl Neuropsychol Adult. 2017;24:23–29. doi: 10.1080/23279095.2015.1065261. PubMed DOI

Ashburner J, Friston KJ. Unified segmentation. Neuroimage. 2005;26:839–851. doi: 10.1016/j.neuroimage.2005.02.018. 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;59:2142–2154. doi: 10.1016/j.neuroimage.2011.10.018. PubMed DOI PMC

Ashburner J, Friston KJ. Voxel-based morphometry–the methods. Neuroimage. 2000;11:805–821. doi: 10.1006/nimg.2000.0582. PubMed DOI

Gorgolewski, K. J. et al. NeuroVault.org: a web-based repository for collecting and sharing unthresholded statistical maps of the human brain. Frontiers in Neuroinformatics9, 10.3389/fninf.2015.00008 (2015). PubMed PMC

Differential effects of deep brain stimulation and levodopa on brain activity in Parkinson's disease