Levodopa and, later, deep brain stimulation (DBS) have become the mainstays of therapy for motor symptoms associated with Parkinson's disease (PD). Although these therapeutic options lead to similar clinical outcomes, the neural mechanisms underlying their efficacy are different. Therefore, investigating the differential effects of DBS and levodopa on functional brain architecture and associated motor improvement is of paramount interest. Namely, we expected changes in functional brain connectivity patterns when comparing levodopa treatment with DBS. Clinical assessment and functional magnetic resonance imaging (fMRI) was performed before and after implanting electrodes for DBS in the subthalamic nucleus (STN) in 13 PD patients suffering from severe levodopa-induced motor fluctuations and peak-of-dose dyskinesia. All measurements were acquired in a within subject-design with and without levodopa treatment, and with and without DBS. Brain connectivity changes were computed using eigenvector centrality (EC) that offers a data-driven and parameter-free approach-similarly to Google's PageRank algorithm-revealing brain regions that have an increased connectivity to other regions that are highly connected, too. Both levodopa and DBS led to comparable improvement of motor symptoms as measured with the Unified Parkinson's Disease Rating Scale motor score (UPDRS-III). However, this similar therapeutic effect was underpinned by different connectivity modulations within the motor system. In particular, EC revealed a major increase of interconnectedness in the left and right motor cortex when comparing DBS to levodopa. This was accompanied by an increase of connectivity of these motor hubs with the thalamus and cerebellum. We observed, for the first time, significant functional connectivity changes when comparing the effects of STN DBS and oral levodopa administration, revealing different treatment-specific mechanisms linked to clinical benefit in PD. Specifically, in contrast to levodopa treatment, STN DBS was associated with increased connectivity within the cortico-thalamo-cerebellar network. Moreover, given the favorable effects of STN DBS on motor complications, the changes in the patients' clinical profile might also contribute to connectivity changes associated with STN-DBS. Understanding the observed connectivity changes may be essential for enhancing the effectiveness of DBS treatment, and for better defining the pathophysiology of the disrupted motor network in PD.

Department of Neurology and Center of Clinical Neuroscience Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Neurology and Center of Clinical Neuroscience Charles University 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic; Department of Stereotactic and Radiation Neurosurgery Na Homolce Hospital Prague Czech Republic

Department of Stereotactic and Radiation Neurosurgery Na Homolce Hospital Prague Czech Republic

Max Planck Institute for Human Cognitive and Brain Sciences Leipzig Germany

Max Planck Institute for Human Cognitive and Brain Sciences Leipzig Germany; Clinic for Cognitive Neurology University Hospital Leipzig Germany

See more in PubMed

Arai N., Yokochi F., Ohnishi T., Momose T., Okiyama R., Taniguchi M., Takahashi H., Matsuda H., Ugawa Y. Mechanisms of unilateral STN-DBS in patients with Parkinson's disease: a PET study. J. Neurol. 2008;255:1236–1243. PubMed

Ashburner J., Friston K.J. Unified segmentation. NeuroImage. 2005;26:839–851. PubMed

Ashkan K., Rogers P., Bergman H., Ughratdar I. Insights into the mechanisms of deep brain stimulation. Nat. Rev. Neurol. 2017;13:548–554. PubMed

Benabid A.L., Pollak P., Hoffmann D., Gervason C., Hommel M., Perret J.E., de Rougemont J., Gao D.M. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 1991;337:403–406. PubMed

Birkmayer W., Hornykiewicz O. The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia. Wien. Klin. Wochenschr. 1961;10:787–788. PubMed

Brin S., Page L. The anatomy of a large-scale hypertextual Web search engine. Comput. Netw. Isdn Syst. 1998;30:107–117.

Bronstein J.M., Tagliati M., Alterman R.L., Lozano A.M., Volkmann J., Stefani A., Horak F.B., Okun M.S., Foote K.D., Krack P. Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch. Neurol. 2011;68:165–171. PubMed PMC

Brunenberg E.J., Moeskops P., Backes W.H., Pollo C., Cammoun L., Vilanova A., Janssen M.L., Visser-Vandewalle V.E., ter Haar Romeny B.M., Thiran J.P., Platel B. Structural and resting state functional connectivity of the subthalamic nucleus: identification of motor STN parts and the hyperdirect pathway. PLoS One. 2012;7 PubMed PMC

Bullmore E., Sporns O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat. Rev. Neurosci. 2009;10:186–198. PubMed

Bullmore E., Sporns O. The economy of brain network organization. Nat. Rev. Neurosci. 2012;13:336–349. PubMed

Carmichael D.W., Pinto S., Limousin-Dowsey P., Thobois S., Allen P.J., Lemieux L., Yousry T., Thornton J.S. Functional MRI with active, fully implanted, deep brain stimulation systems: safety and experimental confounds. NeuroImage. 2007;37:508–517. PubMed

Ceballos-Baumann A.O. Functional imaging in Parkinson's disease: activation studies with PET, fMRI and SPECT. J. Neurol. 2003;250(Suppl. 1):I15–23. PubMed

Chiken S., Nambu A. Mechanism of deep brain stimulation: inhibition, excitation, or disruption? Neuroscientist. 2016;22:313–322. PubMed PMC

Chung S.J., Jeon S.R., Kim S.R., Sung Y.H., Lee M.C. Bilateral effects of unilateral subthalamic nucleus deep brain stimulation in advanced Parkinson's disease. Eur. Neurol. 2006;56:127–132. PubMed

Fling B.W., Benson B.L., Seidler R.D. Transcallosal sensorimotor fiber tract structure-function relationships. Hum. Brain Mapp. 2013;34:384–395. PubMed PMC

Fox M.D., Buckner R.L., Liu H., Chakravarty M.M., Lozano A.M., Pascual-Leone A. Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases. Proc. Natl. Acad. Sci. U. S. A. 2014;111:E4367–4375. PubMed PMC

Friston K.J., Buechel C., Fink G.R., Morris J., Rolls E., Dolan R.J. Psychophysiological and modulatory interactions in neuroimaging. NeuroImage. 1997;6:218–229. PubMed

Friston K.J., Harrison L., Penny W. Dynamic causal modelling. NeuroImage. 2003;19:1273–1302. PubMed

Frobenius G. Sitzungsberichte Der Koniglich Preussischen Akademie Der Wissenschaften. 1912. On matrices from non-negative elements; pp. 456–477.

Hamani C., Saint-Cyr J.A., Fraser J., Kaplitt M., Lozano A.M. The subthalamic nucleus in the context of movement disorders. Brain. 2004;127:4–20. PubMed

Herz D.M., Haagensen B.N., Nielsen S.H., Madsen K.H., Lokkegaard A., Siebner H.R. Resting-state connectivity predicts levodopa-induced dyskinesias in Parkinson's disease. Mov. Disord. 2016;31:521–529. PubMed PMC

Holiga S., Mueller K., Moller H.E., Urgosik D., Ruzicka E., Schroeter M.L., Jech R. Resting-state functional magnetic resonance imaging of the subthalamic microlesion and stimulation effects in Parkinson's disease: indications of a principal role of the brainstem. Neuroimage Clin. 2015;9:264–274. PubMed PMC

Horn A., Reich M., Vorwerk J., Li N., Wenzel G., Fang Q., Schmitz-Hubsch T., Nickl R., Kupsch A., Volkmann J., Kuhn A.A., Fox M.D. Connectivity predicts deep brain stimulation outcome in Parkinson disease. Ann. Neurol. 2017;82:67–78. PubMed PMC

Jahanshahi M., Obeso I., Rothwell J.C., Obeso J.A. A fronto-striato-subthalamic-pallidal network for goal-directed and habitual inhibition. Nat. Rev. Neurosci. 2015;16:719. PubMed

Jech R., Urgosik D., Tintera J., Nebuzelsky A., Krasensky J., Liscak R., Roth J., Ruzicka E. Functional magnetic resonance imaging during deep brain stimulation: a pilot study in four patients with Parkinson's disease. Mov. Disord. 2001;16:1126–1132. PubMed

Jech R., Ruzicka E., Urgosik D., Serranova T., Volfova M., Novakova O., Roth J., Dusek P., Mecir P. Deep brain stimulation of the subthalamic nucleus affects resting EEG and visual evoked potentials in Parkinson's disease. Clin. Neurophysiol. 2006;117:1017–1028. PubMed

Jech R., Mueller K., Urgosik D., Sieger T., Holiga S., Ruzicka F., Dusek P., Havrankova P., Vymazal J., Ruzicka E. The subthalamic microlesion story in Parkinson's disease: electrode insertion-related motor improvement with relative cortico-subcortical hypoactivation in fMRI. PLoS One. 2012;7 PubMed PMC

Jech R., Mueller K., Schroeter M.L., Ruzicka E. Levodopa increases functional connectivity in the cerebellum and brainstem in Parkinson's disease. Brain. 2013;136 PubMed

Kahan J., Urner M., Moran R., Flandin G., Marreiros A., Mancini L., White M., Thornton J., Yousry T., Zrinzo L., Hariz M., Limousin P., Friston K., Foltynie T. Resting state functional MRI in Parkinson's disease: the impact of deep brain stimulation on 'effective' connectivity. Brain. 2014;137:1130–1144. PubMed PMC

Kelly C., de Zubicaray G., Di Martino A., Copland D.A., Reiss P.T., Klein D.F., Castellanos F.X., Milham M.P., McMahon K. l-Dopa modulates functional connectivity in striatal cognitive and motor networks: a double-blind placebo-controlled study. J. Neurosci. 2009;29:7364–7378. PubMed PMC

Knight E.J., Testini P., Min H.K., Gibson W.S., Gorny K.R., Favazza C.P., Felmlee J.P., Kim I., Welker K.M., Clayton D.A., Klassen B.T., Chang S.Y., Lee K.H. Motor and nonmotor circuitry activation induced by subthalamic nucleus deep brain stimulation in patients with Parkinson disease: intraoperative functional magnetic resonance imaging for deep brain stimulation. Mayo Clin. Proc. 2015;90:773–785. PubMed PMC

Kumar R., Lozano A., Sime E., Halket E., Lang A. Comparative effects of unilateral and bilateral subthalamic nucleus deep brain stimulation. Neurology. 1999;53:561–566. PubMed

LeWitt P.A. Levodopa therapy for Parkinson's disease: pharmacokinetics and pharmacodynamics. Mov. Disord. 2015;30:64–72. PubMed

Li Q., Ke Y., Chan Danny C.W., Qian Z.-M., Yung Ken K.L., Ko H., Arbuthnott Gordon W., Yung W.-H. Therapeutic deep brain stimulation in parkinsonian rats directly influences motor cortex. Neuron. 2012;76:1030–1041. PubMed

Linazasoro G., Van Blercom N., Lasa A. Unilateral subthalamic deep brain stimulation in advanced Parkinson's disease. Mov. Disord. 2003;18:713–716. PubMed

Lizarraga K.J., Jagid J.R., Luca C.C. Comparative effects of unilateral and bilateral subthalamic nucleus deep brain stimulation on gait kinematics in Parkinson's disease: a randomized, blinded study. J. Neurol. 2016;263:1652–1656. PubMed

Lohmann G., Muller K., Bosch V., Mentzel H., Hessler S., Chen L., Zysset S., von Cramon D.Y. LIPSIA—a new software system for the evaluation of functional magnetic resonance images of the human brain. Comput. Med. Imaging Graph. 2001;25:449–457. PubMed

Lohmann G., Margulies D.S., 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 PubMed PMC

Lozano A.M., Lipsman N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron. 2013;77:406–424. PubMed

Lozano A.M., Dostrovsky J., Chen R., Ashby P. Deep brain stimulation for Parkinson's disease: disrupting the disruption. Lancet Neurol. 2002;1:225–231. PubMed

McIntyre C.C., Hahn P.J. Network perspectives on the mechanisms of deep brain stimulation. Neurobiol. Dis. 2010;38:329–337. PubMed PMC

McIntyre C.C., Mori S., Sherman D.L., Thakor N.V., Vitek J.L. Electric field and stimulating influence generated by deep brain stimulation of the subthalamic nucleus. Clin. Neurophysiol. 2004;115:589–595. PubMed

Mueller K., Jech R., Schroeter M.L. Deep-brain stimulation for Parkinson's disease. N. Engl. J. Med. 2013;368:482–483. PubMed

Odekerken V.J., van Laar T., Staal M.J., Mosch A., Hoffmann C.F., Nijssen P.C., Beute G.N., van Vugt J.P., Lenders M.W., Contarino M.F., Mink M.S., Bour L.J., van den Munckhof P., Schmand B.A., de Haan R.J., Schuurman P.R., de Bie R.M. Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial. Lancet Neurol. 2013;12:37–44. PubMed

Perron O. On the theory of matrices. Math. Ann. 1907;64:248–263.

Poewe W., Antonini A., Zijlmans J.C., Burkhard P.R., Vingerhoets F. Levodopa in the treatment of Parkinson's disease: an old drug still going strong. Clin. Interv. Aging. 2010;5:229–238. PubMed PMC

Power J.D., Barnes K.A., Snyder A.Z., Schlaggar B.L., Petersen S.E. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. NeuroImage. 2012;59:2142–2154. PubMed PMC

Rezai A.R., Phillips M., Baker K.B., Sharan A.D., Nyenhuis J., Tkach J., Henderson J., Shellock F.G. Neurostimulation system used for deep brain stimulation (DBS): MR safety issues and implications of failing to follow safety recommendations. Investig. Radiol. 2004;39:300–303. PubMed

Ruzicka F., Jech R., Novakova L., Urgosik D., Vymazal J., Ruzicka E. Weight gain is associated with medial contact site of subthalamic stimulation in Parkinson's disease. PLoS One. 2012;7 PubMed PMC

Smith Y., Wichmann T., Factor S.A., DeLong M.R. Parkinson's disease therapeutics: new developments and challenges since the introduction of levodopa. Neuropsychopharmacology. 2012;37:213–246. PubMed PMC

Strafella A.P., Sadikot A.F., Dagher A. Subthalamic deep brain stimulation does not induce striatal dopamine release in Parkinson's disease. Neuroreport. 2003;14:1287–1289. PubMed

Tahmasian M., Bettray L.M., van Eimeren T., Drzezga A., Timmermann L., Eickhoff C.R., Eickhoff S.B., 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. PubMed

Taubert M., Lohmann G., Margulies D.S., Villringer A., Ragert P. Long-term effects of motor training on resting-state networks and underlying brain structure. NeuroImage. 2011;57:1492–1498. PubMed

Tomlinson C.L., Stowe R., Patel S., Rick C., Gray R., Clarke C.E. Systematic review of levodopa dose equivalency reporting in Parkinson's disease. Mov. Disord. 2010;25:2649–2653. PubMed

Warren J.D., Rohrer J.D., Hardy J. Disintegrating brain networks: from syndromes to molecular nexopathies. Neuron. 2012;73:1060–1062. PubMed PMC

Wink A.M., de Munck J.C., van der Werf Y.D., van den Heuvel O.A., 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. PubMed

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

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