title: Subthalamic stimulation modulates cortical motor network activity and synchronization in Parkinson's disease.
abstract: Dynamic modulations of large-scale network activity and synchronization are inherent to a broad spectrum of cognitive processes and are disturbed in neuropsychiatric conditions including Parkinson's disease. Here, we set out to address the motor network activity and synchronization in Parkinson's disease and its modulation with subthalamic stimulation. To this end, 20 patients with idiopathic Parkinson's disease with subthalamic nucleus stimulation were analysed on externally cued right hand finger movements with 1.5-s interstimulus interval. Simultaneous recordings were obtained from electromyography on antagonistic muscles (right flexor digitorum and extensor digitorum) together with 64-channel electroencephalography. Time-frequency event-related spectral perturbations were assessed to determine cortical and muscular activity. Next, cross-spectra in the time-frequency domain were analysed to explore the cortico-cortical synchronization. The time-frequency modulations enabled us to select a time-frequency range relevant for motor processing. On these time-frequency windows, we developed an extension of the phase synchronization index to quantify the global cortico-cortical synchronization and to obtain topographic differentiations of distinct electrode sites with respect to their contributions to the global phase synchronization index. The spectral measures were used to predict clinical and reaction time outcome using regression analysis. We found that movement-related desynchronization of cortical activity in the upper alpha and beta range was significantly facilitated with 'stimulation on' compared to 'stimulation off' on electrodes over the bilateral parietal, sensorimotor, premotor, supplementary-motor, and prefrontal areas, including the bilateral inferior prefrontal areas. These spectral modulations enabled us to predict both clinical and reaction time improvement from subthalamic stimulation. With 'stimulation on', interhemispheric cortico-cortical coherence in the beta band was significantly attenuated over the bilateral sensorimotor areas. Similarly, the global cortico-cortical phase synchronization was attenuated, and the topographic differentiation revealed stronger desynchronization over the (ipsilateral) right-hemispheric prefrontal, premotor and sensorimotor areas compared to 'stimulation off'. We further demonstrated that the cortico-cortical phase synchronization was largely dominated by genuine neuronal coupling. The clinical improvement with 'stimulation on' compared to 'stimulation off' could be predicted from this cortical decoupling with multiple regressions, and the reduction of synchronization over the right prefrontal area showed a linear univariate correlation with clinical improvement. Our study demonstrates wide-spread activity and synchronization modulations of the cortical motor network, and highlights subthalamic stimulation as a network-modulating therapy. Accordingly, subthalamic stimulation may release bilateral cortical computational resources by facilitating movement-related desynchronization. Moreover, the subthalamic nucleus is critical to balance inhibitory and facilitatory cortical players within the motor program.
authors.affiliation: 1 German Centre of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany 2 Department for Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany 3 Werner Reichardt Centre for Integrative Neuroscience, 72076 Tübingen, Germany daniel.weiss@uni-tuebingen.de alireza.gharabaghi@uni-tuebingen.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weiss
authors.affiliation: 1 German Centre of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany 2 Department for Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany 3 Werner Reichardt Centre for Integrative Neuroscience, 72076 Tübingen, Germany.
authors.forename: Rosa
authors.initials: R
authors.lastname: Klotz
authors.affiliation: 4 Foetal Medicine Institute, Division of Foetal and Transitional Medicine, Children's National Health System, M3118C Washington, DC, USA.
authors.forename: Rathinaswamy B
authors.initials: RB
authors.lastname: Govindan
authors.affiliation: 1 German Centre of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany 2 Department for Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany 3 Werner Reichardt Centre for Integrative Neuroscience, 72076 Tübingen, Germany.
authors.forename: Marlieke
authors.initials: M
authors.lastname: Scholten
authors.affiliation: 3 Werner Reichardt Centre for Integrative Neuroscience, 72076 Tübingen, Germany 5 Division of Functional and Restorative Neurosurgery, Department of Neurosurgery, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Naros
authors.affiliation: 6 Institute of Medical Psychology and Behavioural Neurobiology, University of Tübingen, 72076 Tübingen, Germany 7 TECNALIA, Health Technologies, 200003 San Sebastian, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Ramos-Murguialday
authors.affiliation: 1 German Centre of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany 2 Department for Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Bunjes
authors.affiliation: 8 Clinical Epidemiology and Applied Biometry, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Meisner
authors.affiliation: 3 Werner Reichardt Centre for Integrative Neuroscience, 72076 Tübingen, Germany 9 Department of Psychiatry and Psychotherapy, Neurophysiology & Interventional Neuropsychiatry, 72076 Tübingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Plewnia
authors.affiliation: 1 German Centre of Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany 2 Department for Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany 3 Werner Reichardt Centre for Integrative Neuroscience, 72076 Tübingen, Germany 10 Clinical and Experimental Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg and Centre Hospitalier de Luxembourg (CHL), 1210 Luxembourg, Luxembourg.
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.affiliation: 3 Werner Reichardt Centre for Integrative Neuroscience, 72076 Tübingen, Germany 5 Division of Functional and Restorative Neurosurgery, Department of Neurosurgery, University of Tübingen, 72076 Tübingen, Germany daniel.weiss@uni-tuebingen.de alireza.gharabaghi@uni-tuebingen.de.
authors.forename: Alireza
authors.initials: A
authors.lastname: Gharabaghi
mesh_terms: D000328:Adult; D000368:Aged; D000978:Antiparkinson Agents / Q000627:therapeutic use; D003344:Cortical Synchronization / Q000187:drug effects / Q000502:physiology*; D046690:Deep Brain Stimulation / Q000379:methods*; D019054:Evoked Potentials, Motor / Q000502:physiology; D005260:Female; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000503:physiopathology*; D009415:Nerve Net / Q000503:physiopathology; D009434:Neural Pathways / Q000503:physiopathology*; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D011597:Psychomotor Performance / Q000187:drug effects; D020530:Subthalamus / Q000502:physiology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa
keywords: Parkinson’s disease; deep brain stimulation; subthalamic nucleus; synchronization, cortex