The aim of this work was to study the effect of deep brain stimulation of the subthalamic nucleus (STN-DBS) on the subnetwork of subcortical and cortical motor regions and on the whole brain connectivity using the functional connectivity analysis in Parkinson's disease (PD). The high-density source space EEG was acquired and analyzed in 43 PD subjects in DBS on and DBS off stimulation states (off medication) during a cognitive-motor task. Increased high gamma band (50-100 Hz) connectivity within subcortical regions and between subcortical and cortical motor regions was significantly associated with the Movement Disorders Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III improvement after DBS. Whole brain neural correlates of cognitive performance were also detected in the high gamma (50-100 Hz) band. A whole brain multifrequency connectivity profile was found to classify optimal and suboptimal responders to DBS with a positive predictive value of 0.77, negative predictive value of 0.55, specificity of 0.73, and sensitivity of 0.60. Specific connectivity patterns related to PD, motor symptoms improvement after DBS, and therapy responsiveness predictive connectivity profiles were uncovered.

1st Department of Neurology Masaryk University School of Medicine St Anne's Hospital Brno Czech Republic

Brain and Mind Research Program Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Complex Systems Institute of Computer Science Czech Academy of Sciences Prague Czech Republic

Faculty of Informatics Masaryk University Brno Czech Republic

National Institute of Mental Health Klecany Czech Republic

See more in PubMed

for Parkinson’s Disease Study Group. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the Globus Pallidus in Parkinson’s disease. N. Engl. J. Med.345, 956–963 (2001). PubMed

Rodriguez-Oroz, M. C. et al. Bilateral deep brain stimulation in Parkinson’s disease: A multicentre study with 4 years follow-up. Brain128, 2240–2249 (2005). PubMed

Deuschl, G. et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N. Engl. J. Med.355, 896–908 (2006). PubMed

Moro, E. et al. Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson’s disease. Mov. Disord.25, 578–586 (2010). PubMed

Lozano, A. M. et al. Deep brain stimulation: Current challenges and future directions. Nat. Rev. Neurol.15, 148–160 (2019). PubMed PMC

Temel, Y. et al. Behavioural changes after bilateral subthalamic stimulation in advanced Parkinson disease: A systematic review. Parkinsonism Relat. Disord12, 265–272 (2006). PubMed

Voon, V., Kubu, C., Krack, P., Houeto, J. L. & Tröster A. I. Deep brain stimulation: Neuropsychological and neuropsychiatric issues. Mov. Disord21, S305–S327 (2006). PubMed

Witt, K. et al. Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson’s disease: A randomised, multicentre study. Lancet Neurol.7, 605–614 (2008). PubMed

Little, S. et al. Adaptive deep brain stimulation in advanced Parkinson disease. Ann. Neurol.74, 449–457 (2013). PubMed PMC

Habets, J. G. V. et al. An update on adaptive deep brain stimulation in Parkinson’s disease. Mov. Disord.33, 1834–1843 (2018). PubMed PMC

Tinkhauser, G. et al. The modulatory effect of adaptive deep brain stimulation on beta bursts in Parkinson’s disease. Brain140, 1053–1067 (2017). PubMed PMC

Alonso-Frech, F. et al. Slow oscillatory activity and levodopa-induced dyskinesias in Parkinson’s disease. Brain129, 1748–1757 (2006). PubMed

Chen, C. C. et al. Complexity of subthalamic 13–35 hz oscillatory activity directly correlates with clinical impairment in patients with Parkinson’s disease. Exp. Neurol.224, 234–240 (2010). PubMed

Oswal, A. et al. Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting state networks in Parkinson’s disease. Brain139, 1482–1496 (2016). PubMed PMC

Steiner, L. A. et al. Subthalamic beta dynamics mirror parkinsonian bradykinesia months after neurostimulator implantation. Mov. Disord.32, 1183–1190 (2017). PubMed PMC

Kühn, A. A., Kupsch, A., Schneider, G. H. & Brown, P. Reduction in subthalamic 8–35 hz oscillatory activity correlates with clinical improvement in Parkinson’s disease. Eur. J. Neurosci.23, 1956–1960 (2006). PubMed

van Wijk, B. C. M. et al. Subthalamic nucleus phase–amplitude coupling correlates with motor impairment in Parkinson’s disease. Clin. Neurophysiol.127, 2010–2019 (2016). PubMed PMC

Bočková, M. et al. Coupling between beta band and high frequency oscillations as a clinically useful biomarker for DBS. NPJ Parkinsons Dis.10, 40 (2024). PubMed PMC

López-Azcárate, J. et al. Coupling between beta and high-frequency activity in the human subthalamic nucleus may be a pathophysiological mechanism in Parkinson’s disease. J. Neurosci.30, 6667–6677 (2010). PubMed PMC

Litvak, V., Florin, E., Tamás, G., Groppa, S. & Muthuraman, M. EEG and MEG primers for tracking DBS network effects. Neuroimage224, 117447 (2021). PubMed

Bočková, M. & Rektor, I. Impairment of brain functions in Parkinson’s disease reflected by alterations in neural connectivity in EEG studies: A viewpoint. Clin. Neurophysiol.130, 239–247 (2019). PubMed

Markser, A. et al. Deep brain stimulation and cognitive decline in Parkinson’s disease: The predictive value of electroencephalography. J. Neurol.262, 2275–2284 (2015). PubMed

Yakufujiang, M. et al. Predictive potential of preoperative electroencephalogram for neuropsychological change following subthalamic nucleus deep brain stimulation in Parkinson’s disease. Acta Neurochir. (Wien)161, 2049–2058 (2019). PubMed

Onofrj, M., Espay, A. J., Bonanni, L., Delli Pizzi, S. & Sensi, S. L. Hallucinations, somatic-functional disorders of PD-DLB as expressions of thalamic dysfunction. Mov. Disord.34, 1100–1111 (2019). PubMed PMC

Geraedts, V. J. et al. Machine learning for automated EEG-based biomarkers of cognitive impairment during deep brain stimulation screening in patients with Parkinson’s Disease. Clin. Neurophysiol.132, 1041–1048 (2021). PubMed

Bočková, M. et al. Cortical network organization reflects clinical response to subthalamic nucleus deep brain stimulation in Parkinson’s disease. Hum. Brain Mapp.42, 5626–5635 (2021). PubMed PMC

Polich, J. Updating P300: An integrative theory of P3a and P3b. Clin. Neurophysiol.118, 2128–2148 (2007). PubMed PMC

Bočková, M. et al. Oscillatory changes in cognitive networks activated during a three-stimulus visual paradigm: An intracerebral study. Clin. Neurophysiol.124, 283–291 (2013). PubMed

Fournier, L. R. et al. Which task will we choose first? Precrastination and cognitive load in task ordering. Atten. Percept. Psychophys81, 489–503 (2019). PubMed

Horn, A. & Kühn, A. A. Lead-DBS: A toolbox for deep brain stimulation electrode localizations and visualizations. Neuroimage107, 127–135 (2015). PubMed

Ewert, S. et al. Toward defining deep brain stimulation targets in MNI space: A subcortical atlas based on multimodal MRI, histology and structural connectivity. Neuroimage170, 271–282 (2018). PubMed

Delorme, A. & Makeig, S. EEGLAB: An open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J. Neurosci. Methods134, 9–21 (2004). PubMed

Coito, A., Michel, C. M., Vulliemoz, S. & Plomp, G. Directed functional connections underlying spontaneous brain activity. Hum. Brain Mapp.40, 879–888 (2019). PubMed PMC

Zaldivar, D., Goense, J., Lowe, S. C., Logothetis, N. K. & Panzeri, S. Dopamine is signaled by mid-frequency oscillations and boosts output layers visual information in visual cortex. Curr. Biol.28, 224–235 (2018). PubMed

Plesinger, F., Jurco, J., Halamek, J. & Jurak, P. SignalPlant: An open signal processing software platform. Physiol. Meas.37, N38 (2016). PubMed

Lio, G., Thobois, S., Ballanger, B., Lau, B. & Boulinguez, P. Removing deep brain stimulation artifacts from the electroencephalogram: Issues, recommendations and an open-source toolbox. Clin. Neurophysiol.129, 2170–2185 (2018). PubMed

Lamoš, M. et al. The effect of deep brain stimulation in Parkinson’s disease reflected in EEG microstates. NPJ Parkinsons Dis.9, 63 (2023). PubMed PMC

Bočková, M. et al. Suboptimal response to STN-DBS in Parkinson’s disease can be identified via reaction times in a motor cognitive paradigm. J. Neural Transm127, 1579–1588 (2020). PubMed

Chaumon, M., Bishop, D. V. M. & Busch, N. A. A practical guide to the selection of independent components of the electroencephalogram for artifact correction. J. Neurosci. Methods250, 47–63 (2015). PubMed

Brunet, D., Murray, M. M. & Michel, C. M. Spatiotemporal analysis of multichannel EEG: CARTOOL. Comput Intell Neurosci 1–15 (2011). (2011). PubMed PMC

Tzourio-Mazoyer, N. et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage15, 273–289 (2002). PubMed

Coito, A., Michel, C. M., Van Mierlo, P., Vulliemoz, S. & Plomp, G. Directed functional brain connectivity based on EEG source imaging: Methodology and application to temporal lobe epilepsy. IEEE Trans. Biomed. Eng.63, 2619–2628 (2016). PubMed

Litvak, V. et al. Movement-related changes in local and long-range synchronization in Parkinson’s disease revealed by simultaneous magnetoencephalography and intracranial recordings. J. Neurosci.32, 10541–10553 (2012). PubMed PMC

Wiest, C. et al. Finely-tuned gamma oscillations: Spectral characteristics and links to dyskinesia. Exp. Neurol.351, 113999 (2022). PubMed PMC

Seeber, M. et al. Subcortical electrophysiological activity is detectable with high-density EEG source imaging. Nat. Commun.10, 753 (2019). PubMed PMC

Stam, C. J., Nolte, G. & Daffertshofer, A. Phase lag index: Assessment of functional connectivity from multi channel EEG and MEG with diminished bias from common sources. Hum. Brain Mapp.28, 1178–1193 (2007). PubMed PMC

Cohen, M. X. Effects of time lag and frequency matching on phase-based connectivity. J. Neurosci. Methods250, 137–146 (2015). PubMed

Birot, G. et al. Head model and electrical source imaging: A study of 38 epileptic patients. Neuroimage Clin.5, 77–83 (2014). PubMed PMC

Michel, C. M. & Brunet, D. EEG source imaging: A practical review of the analysis steps. Front. Neurol.10, 325 (2019). PubMed PMC

Kahan, J. et al. Resting state functional MRI in Parkinson’s disease: The impact of deep brain stimulation on ‘effective’connectivity. Brain137, 1130–1144 (2014). PubMed PMC

Middlebrooks, E. H. et al. Differences in functional connectivity profiles as a predictor of response to anterior thalamic nucleus deep brain stimulation for epilepsy: A hypothesis for the mechanism of action and a potential biomarker for outcomes. Neurosurg. Focus45, E7 (2018). PubMed

Younce, J. R. et al. Resting-state functional connectivity predicts STN DBS Clinical Response. Mov. Disord.36, 662–671 (2021). PubMed PMC

Horn, A. et al. Connectivity predicts deep brain stimulation outcome in P arkinson disease. Ann. Neurol.82, 67–78 (2017). PubMed PMC

Schneider, L., Seeger, V., Timmermann, L. & Florin, E. Electrophysiological resting state networks of predominantly akinetic-rigid Parkinson patients: Effects of dopamine therapy. Neuroimage Clin.25, 102147 (2020). PubMed PMC

Horn, A., Neumann, W. J., Degen, K., Schneider, G. H. & Kühn, A. A. Toward an electrophysiological sweet spot for deep brain stimulation in the subthalamic nucleus. Hum. Brain Mapp.38, 3377–3390 (2017). PubMed PMC

Sobesky, L. et al. Subthalamic and pallidal deep brain stimulation: Are we modulating the same network? Brain145, 251–262 (2022). PubMed

Fumagalli, M. et al. Conflict-dependent dynamic of subthalamic nucleus oscillations during moral decisions. Soc. Neurosci.6, 243–256 (2011). PubMed

Huebl, J. et al. Oscillatory subthalamic nucleus activity is modulated by dopamine during emotional processing in Parkinson’s disease. Cortex60, 69–81 (2014). PubMed

Welter, M. L. et al. Basal ganglia dysfunction in OCD: Subthalamic neuronal activity correlates with symptoms severity and predicts high-frequency stimulation efficacy. Transl Psychiatry1, e5–e5 (2011). PubMed PMC

Rappel, P. et al. Subthalamic theta activity: A novel human subcortical biomarker for obsessive compulsive disorder. Transl Psychiatry8, 118 (2018). PubMed PMC

Brown, P. Oscillatory nature of human basal ganglia activity: Relationship to the pathophysiology of Parkinson’s disease. Mov. Disord18, 357–363 (2003). PubMed

Androulidakis, A. G. et al. Dopaminergic therapy promotes lateralized motor activity in the subthalamic area in Parkinson’s disease. Brain130, 457–468 (2007). PubMed

Doyle, L. M. F. et al. Levodopa-induced modulation of subthalamic beta oscillations during self-paced movements in patients with Parkinson’s disease. Eur. J. Neurosci.21, 1403–1412 (2005). PubMed

Kühn, A. A. et al. Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance. Brain127, 735–746 (2004). PubMed

Abbruzzese, G. & Berardelli, A. Sensorimotor integration in movement disorders. Mov. Disord.18, 231–240 (2003). PubMed

Cole, R. C., Okine, D. N., Yeager, B. E. & Narayanan, N. S. Neuromodulation of cognition in Parkinson’s disease. Prog Brain Res.269, 435–455 (2022). PubMed PMC

Brittain, J. S. & Cagnan, H. Recent trends in the Use of Electrical Neuromodulation in Parkinson’s Disease. Curr. Behav. Neurosci. Rep.5, 170–178 (2018). PubMed PMC

You, Z. et al. Efforts of subthalamic nucleus deep brain stimulation on cognitive spectrum: From explicit to implicit changes in the patients with Parkinson’s disease for 1 year. CNS Neurosci. Ther.26, 972–980 (2020). PubMed PMC

Vanegas-Arroyave, N. et al. Tractography patterns of subthalamic nucleus deep brain stimulation. Brain139, 1200–1210 (2016). PubMed PMC

Albano, L. et al. Functional connectivity in Parkinson’s disease candidates for deep brain stimulation. NPJ Parkinsons Dis.8, 4 (2022). PubMed PMC

Yousif, N., Bain, P. G., Nandi, D. & Borisyuk, R. A population model of deep brain stimulation in movement disorders from circuits to cells. Front. Hum. Neurosci.14, 55 (2020). PubMed PMC

Meier, J. M. et al. Virtual deep brain stimulation: Multiscale co-simulation of a spiking basal ganglia model and a whole-brain mean-field model with the virtual brain. Exp. Neurol.354, 114111 (2022). PubMed

Maith, O. et al. A computational model-based analysis of basal ganglia pathway changes in Parkinson’s disease inferred from resting-state fMRI. Eur. J. Neurosci.53, 2278–2295 (2021). PubMed

Xia, M., Wang, J. & He, Y. BrainNet Viewer: A network visualization tool for human brain connectomics. PLoS One8, e68910 (2013). PubMed PMC