Contents lists available at ScienceDirect Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis Cerebello-striatal interaction mediates effects of subthalamic nucleus deep brain stimulation in Parkinson's disease Henrike Hanssen a,b,1 , Julia Steinhardt a,c,1 , Alexander Münchau c , Arkan Al-Zubaidi a , Elinor Tzvi d , Marcus Heldmann a,e , Peter Schramm f , Alexander Neumann f , Dirk Rasche g , Assel Saryyeva h , Jürgen Voges i,j , Imke Galazky k , Lars Büntjen i , Hans-Jochen Heinze k , Joachim K. Krauss h , Volker Tronnier g , Thomas F. Münte a,e , Norbert Brüggemann a,c,∗ a Department of Neurology, University of Lübeck, Lübeck, Germany b Institute of Neurogenetics, University of Lübeck, Lübeck, Germany c Department of Internal Medicine, University of Lübeck, Lübeck, Germany d Department of Neurology, University of Leipzig, Leipzig, Germany e Institute of Psychology II, University of Lübeck, Lübeck, Germany f Institute of Neuroradiology, University of Lübeck, Lübeck, Germany g Department of Neurosurgery, University of Lübeck, Lübeck, Germany h Department of Neurosurgery, Medical School Hanover, MHH, Hanover, Germany i Department of Stereotactic Neurosurgery, University Hospital Magdeburg, Magdeburg, Germany j Leibniz Institute of Neurobiology, Magdeburg, Germany k Department of Neurology, University Hospital Magdeburg, Magdeburg, Germany ARTICLE INFO Keywords: Deep brain stimulation Subthalamic nucleus Striatum Cerebellum Dynamic causal modelling ABSTRACT Background: In Parkinson's disease (PD), dopamine replacement therapy (DRT) enhances the effective con- nectivity of the prefrontal cortex (PFC) and supplementary motor area (SMA). The clinical effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) go beyond DRT effects including highly beneficial tremor suppression. Objectives: Here, we aimed to determine DBS-related changes of a motor network using resting state fMRI in PD patients with chronic STN DBS. Methods: In a repeated-measurement design, 26 medicated PD patients (60.9 years (SD 8.9)) were investigated using resting state fMRI while bipolar STN stimulation was (i) active or (ii) switched off, and dynamic causal modelling was subsequently performed. Results: DBS improved the MDS-UPDRS-III score by 26.4% (DBS ON/Med ON vs. DBS OFF/Med ON). Active stimulation resulted in an increased effective connectivity from cerebellum to putamen (p = 0.00118). In ad- dition, there was a stronger coupling from PFC to cerebellum (p = 0.021), as well as from cerebellum to SMA (p = 0.043) on an uncorrected level. Coupling strength from PFC to cerebellum correlated with the DBS-related change of the resting tremor subscore (r = 0.54, p = 0.031). Self-connections increased as a function of DBS in the right PFC, PMC, SMA, M1, thalamus and left cerebellum. Conclusions: DBS-related improvement of Parkinsonian signs appears to be driven by an interaction between the cerebellum and the putamen. Resting tremor suppression may be related to an enhanced prefronto-cerebellar network. Activation of the mesial premotor loop (PFC-SMA) as seen in DRT may thus be secondary due to the primary modulation of cerebellar networks. 1. Introduction Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an important therapeutic option in patients with Parkinson's disease (PD) and clinically relevant motor fluctuations, drug-resistant tremor, or intolerable side effects of Antiparkinsonian drugs. As one of https://doi.org/10.1016/j.parkreldis.2019.09.003 Received 18 January 2019; Received in revised form 30 August 2019; Accepted 2 September 2019 ∗ Corresponding author. Dept. of Neurology and Institute of Neurogenetics, University of Lübeck; Ratzeburger Allee, 23538, Lübeck, Germany. E-mail address: norbert.brueggemann@neuro.uni-luebeck.de (N. Brüggemann). 1 These authors contributed equally. Parkinsonism and Related Disorders xxx (xxxx) xxx–xxx 1353-8020/ © 2019 Elsevier Ltd. All rights reserved. Please cite this article as: Henrike Hanssen, et al., Parkinsonism and Related Disorders, https://doi.org/10.1016/j.parkreldis.2019.09.003