Connectivity Profile for Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson Disease
Corresponding Author
Mallory L. Hacker PhD, MSCI
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
Address correspondence to Dr Hacker, Department of Neurology, Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, 440 Crystal Terrace, 3319 West End Ave, Nashville, TN 37203. E-mail: [email protected]
Search for more papers by this authorNanditha Rajamani MSc
Movement Disorder and Neuromodulation Unit, Department of Neurology, Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Free University of Berlin and Humboldt University of Berlin, Berlin, Germany
Search for more papers by this authorClemens Neudorfer MD
Center for Brain Circuit Therapeutics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorBarbara Hollunder MSc
Movement Disorder and Neuromodulation Unit, Department of Neurology, Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Free University of Berlin and Humboldt University of Berlin, Berlin, Germany
Einstein Center for Neurosciences Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany
Berlin School of Mind and Brain, Humboldt University of Berlin, Berlin, Germany
Search for more papers by this authorSimon Oxenford
Movement Disorder and Neuromodulation Unit, Department of Neurology, Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Free University of Berlin and Humboldt University of Berlin, Berlin, Germany
Search for more papers by this authorNingfei Li PhD
Movement Disorder and Neuromodulation Unit, Department of Neurology, Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Free University of Berlin and Humboldt University of Berlin, Berlin, Germany
Search for more papers by this authorAlice L. Sternberg ScM
Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA
Search for more papers by this authorThomas L. Davis MD
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
Search for more papers by this authorPeter E. Konrad MD, PhD
Department of Neurosurgery, West Virginia University, Morgantown, WV, USA
Search for more papers by this authorAndreas Horn MD, PhD
Movement Disorder and Neuromodulation Unit, Department of Neurology, Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Free University of Berlin and Humboldt University of Berlin, Berlin, Germany
Center for Brain Circuit Therapeutics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Department of Neurosurgery and Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorDavid Charles MD
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
Search for more papers by this authorCorresponding Author
Mallory L. Hacker PhD, MSCI
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
Address correspondence to Dr Hacker, Department of Neurology, Department of Physical Medicine and Rehabilitation, Vanderbilt University Medical Center, 440 Crystal Terrace, 3319 West End Ave, Nashville, TN 37203. E-mail: [email protected]
Search for more papers by this authorNanditha Rajamani MSc
Movement Disorder and Neuromodulation Unit, Department of Neurology, Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Free University of Berlin and Humboldt University of Berlin, Berlin, Germany
Search for more papers by this authorClemens Neudorfer MD
Center for Brain Circuit Therapeutics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorBarbara Hollunder MSc
Movement Disorder and Neuromodulation Unit, Department of Neurology, Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Free University of Berlin and Humboldt University of Berlin, Berlin, Germany
Einstein Center for Neurosciences Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany
Berlin School of Mind and Brain, Humboldt University of Berlin, Berlin, Germany
Search for more papers by this authorSimon Oxenford
Movement Disorder and Neuromodulation Unit, Department of Neurology, Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Free University of Berlin and Humboldt University of Berlin, Berlin, Germany
Search for more papers by this authorNingfei Li PhD
Movement Disorder and Neuromodulation Unit, Department of Neurology, Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Free University of Berlin and Humboldt University of Berlin, Berlin, Germany
Search for more papers by this authorAlice L. Sternberg ScM
Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA
Search for more papers by this authorThomas L. Davis MD
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
Search for more papers by this authorPeter E. Konrad MD, PhD
Department of Neurosurgery, West Virginia University, Morgantown, WV, USA
Search for more papers by this authorAndreas Horn MD, PhD
Movement Disorder and Neuromodulation Unit, Department of Neurology, Department of Neurology, Charité–Universitätsmedizin Berlin, corporate member of Free University of Berlin and Humboldt University of Berlin, Berlin, Germany
Center for Brain Circuit Therapeutics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Department of Neurosurgery and Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Search for more papers by this authorDavid Charles MD
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
Search for more papers by this authorAndreas Horn and David Charles contributed equally to this work.
Abstract
Objective
This study was undertaken to describe relationships between electrode localization and motor outcomes from the subthalamic nucleus (STN) deep brain stimulation (DBS) in early stage Parkinson disease (PD) pilot clinical trial.
Methods
To determine anatomical and network correlates associated with motor outcomes for subjects randomized to early DBS (n = 14), voxelwise sweet spot mapping and structural connectivity analyses were carried out using outcomes of motor progression (Unified Parkinson Disease Rating Scale Part III [UPDRS-III] 7-day OFF scores [∆baseline➔24 months, MedOFF/StimOFF]) and symptomatic motor improvement (UPDRS-III ON scores [%∆baseline➔24 months, MedON/StimON]).
Results
Sweet spot mapping revealed a location associated with slower motor progression in the dorsolateral STN (anterior/posterior commissure coordinates: 11.07 ± 0.82mm lateral, 1.83 ± 0.61mm posterior, 3.53 ± 0.38mm inferior to the midcommissural point; Montreal Neurological Institute coordinates: +11.25, −13.56, −7.44mm). Modulating fiber tracts from supplementary motor area (SMA) and primary motor cortex (M1) to the STN correlated with slower motor progression across STN DBS subjects, whereas fiber tracts originating from pre-SMA and cerebellum were negatively associated with motor progression. Robustness of the fiber tract model was demonstrated in leave-one-patient-out (R = 0.56, p = 0.02), 5-fold (R = 0.50, p = 0.03), and 10-fold (R = 0.53, p = 0.03) cross-validation paradigms. The sweet spot and fiber tracts associated with motor progression revealed strong similarities to symptomatic motor improvement sweet spot and connectivity in this early stage PD cohort.
Interpretation
These results suggest that stimulating the dorsolateral region of the STN receiving input from M1 and SMA (but not pre-SMA) is associated with slower motor progression across subjects receiving STN DBS in early stage PD. This finding is hypothesis-generating and must be prospectively tested in a larger study. ANN NEUROL 2023;94:271–284
Potential Conflicts of Interest
M.L.H. and D.C. are shareholders of Arena Therapeutics, a company focused on advancing research of DBS for the treatment of patients recently diagnosed with PD. P.E.K. has equity ownership in Neurotargeting, which has developed a system that facilitates the operative phases of DBS procedures. A.H. has received lecturing fees from Boston Scientific, which manufactures DBS systems. The other authors have nothing to report.
References
- 1Schuepbach WMM, Rau J, Knudsen K, et al. Neurostimulation for Parkinson's disease with early motor complications. N Engl J Med 2013; 368: 610–622. https://doi.org/10.1056/nejmoa1205158.
- 2Deuschl GG, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med 2006; 355: 896–908. https://doi.org/10.1056/nejmoa060281.
- 3Weaver FM, Follett KA, Stern M, et al. Randomized trial of deep brain stimulation for Parkinson disease: thirty-six-month outcomes. Neurology 2012; 79: 55–65. https://doi.org/10.1212/WNL.0b013e31825dcdc1.
- 4Charles PD, Van Blercom N, Krack P, et al. Predictors of effective bilateral subthalamic nucleus stimulation for PD. Neurology 2002; 59: 932–934. https://doi.org/10.1212/WNL.59.6.932.
- 5Welter ML, Houeto JL, Du Montcel ST, et al. Clinical predictive factors of subthalamic stimulation in Parkinson's disease. Brain 2002; 125: 575–583. https://doi.org/10.1093/brain/awf050.
- 6Horn A, Li N, Dembek TA, et al. Lead-DBS v2: towards a comprehensive pipeline for deep brain stimulation imaging. Neuroimage 2019; 184: 293–316. https://doi.org/10.1016/j.neuroimage.2018.08.068.
- 7Caire F, Ranoux D, Guehl D, et al. A systematic review of studies on anatomical position of electrode contacts used for chronic subthalamic stimulation in Parkinson's disease. Acta Neurochir (Wien) 2013; 155: 1647–1654. https://doi.org/10.1007/s00701-013-1782-1.
- 8Neudorfer C, Kroneberg D, Al-Fatly B, et al. Personalizing deep brain stimulation using advanced imaging sequences. Ann Neurol 2022; 91: 613–628. https://doi.org/10.1002/ana.26326.
- 9Butson CR, Maks CB, McIntyre CC. Sources and effects of electrode impedance during deep brain stimulation. Clin Neurophysiol 2006; 117: 447–454. https://doi.org/10.1016/J.CLINPH.2005.10.007.
- 10Akram H, Georgiev D, Mahlknecht P, et al. Subthalamic deep brain stimulation sweet spots and hyperdirect cortical connectivity in Parkinson's disease. Neuroimage 2017; 158: 332–345. https://doi.org/10.1016/j.neuroimage.2017.07.012.
- 11Lozano AM, Lipsman N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 2013; 77: 406–424. https://doi.org/10.1016/J.NEURON.2013.01.020.
- 12Horn A, Reich M, Vorwerk J, et al. Connectivity predicts deep brain stimulation outcome in Parkinson disease. Ann Neurol 2017; 82: 67–78. https://doi.org/10.1002/ana.24974.
- 13Sobesky L, Goede L, Odekerken VJJ, et al. Subthalamic and pallidal deep brain stimulation: are we modulating the same network? Brain 2022; 145: 251–262. https://doi.org/10.1093/brain/awab258.
- 14Jakobs M, Fomenko A, Lozano AM, Kiening KL. Cellular, molecular, and clinical mechanisms of action of deep brain stimulation—a systematic review on established indications and outlook on future developments. EMBO Mol Med 2019; 11: 1–18. https://doi.org/10.15252/emmm.201809575.
- 15Avecillas-Chasin JM, Honey CR. Modulation of nigrofugal and pallidofugal pathways in deep brain stimulation for parkinson disease. Neurosurgery 2020; 86: E387–E397. https://doi.org/10.1093/neuros/nyz544.
- 16Charles D, Konrad PE, Neimat JS, et al. Subthalamic nucleus deep brain stimulation in early stage Parkinson's disease. Park Relat Disord 2014; 20: 731–737. https://doi.org/10.1016/j.parkreldis.2014.03.019.
- 17Charles D, Tolleson C, Davis TL, et al. Pilot study assessing the feasibility of applying bilateral deep brain stimulation in very early stages of Parkinson's disease: study design and rationale. J Parkinsons Dis 2012; 2: 215–223. file:///0/Unknown/0UnknownUnknown_12.pdf.
- 18Kahn E, D'Haese PF, Dawant B, et al. Deep brain stimulation in early stage Parkinson's disease: operative experience from a prospective randomised clinical trial. J Neurol Neurosurg Psychiatry 2011; 83: 164–170. https://doi.org/10.1136/jnnp-2011-300008.
- 19Camalier CR, Konrad PE, Gill CE, et al. Methods for surgical targeting of the STN in early-stage Parkinson's disease. Front Neurol 2014; 5:5. https://doi.org/10.3389/fneur.2014.00025.
- 20Hacker ML, Turchan M, Heusinkveld LE, et al. Deep brain stimulation in early-stage Parkinson disease: five-year outcomes. Neurology 2020; 95: E393–E401. https://doi.org/10.1212/WNL.0000000000009946.
- 21Hacker ML, Meystedt JC, Turchan M, et al. Eleven-year outcomes of deep brain stimulation in early-stage Parkinson disease. Neuromodulation Technol Neural Interface 2023; 26: 451–458. https://doi.org/10.1016/j.neurom.2022.10.051.
- 22Tomlinson CL, Stowe R, Patel S, et al. Systematic review of levodopa does equivalency reporting in Parkinson's disease. Mov Disord 2010; 25: 2649–2685. https://doi.org/10.1002/mds.23429.
- 23Avants BB, Tustison NJ, Song G, et al. A reproducible evaluation of ANTs similarity metric performance in brain image registration. Neuroimage 2011; 54: 2033–2044. https://doi.org/10.1016/j.neuroimage.2010.09.025.
- 24Avants BB, Epstein CL, Grossman M, Gee JC. Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain. Med Image Anal 2008; 12: 26–41. https://doi.org/10.1016/j.media.2007.06.004.
- 25Ewert S, Plettig P, Li N, et al. Toward defining deep brain stimulation targets in MNI space: a subcortical atlas based on multimodal MRI, histology and structural connectivity. Neuroimage 2018; 170: 271–282. https://doi.org/10.1016/j.neuroimage.2017.05.015.
- 26Husch A, Petersen MV, Gemmar P, et al. PaCER – A fully automated method for electrode trajectory and contact reconstruction in deep brain stimulation. NeuroImage Clin 2018; 17: 80–89. https://doi.org/10.1016/j.nicl.2017.10.004.
- 27Treu S, Strange B, Oxenford S, et al. Deep brain stimulation: imaging on a group level. Neuroimage. 2020; 219:117018. https://doi.org/10.1016/j.neuroimage.2020.117018.
- 28Åström M, Diczfalusy E, Martens H, Wårdell K. Relationship between neural activation and electric field distribution during deep brain stimulation. IEEE Trans Biomed Eng. 2015; 62: 664–672.
- 29Rajamani N, Hollunder B, Odekerken V, et al. Symptom specific tractography correlates with, and can be used to suggest optimal parameters for DBS programming and surgery. Abstract presented atI DBS expert summit. Würzburg, Germany. 2022.
- 30Horn A, Reich MM, Ewert S, et al. Optimal deep brain stimulation sites and networks for cervical vs. generalized dystonia. Proc Natl Acad Sci U S A 2022; 119: 1–11. https://doi.org/10.1073/pnas.2114985119.
- 31Horn A, Kühn AA, Merkl A, et al. Probabilistic conversion of neurosurgical DBS electrode coordinates into MNI space. Neuroimage 2017; 150: 395–404. https://doi.org/10.1016/j.neuroimage.2017.02.004.
- 32Bejjani BP, Dormont D, Pidoux B, et al. Bilateral subthalamic stimulation for Parkinson's disease by using three-dimensional stereotactic magnetic resonance imaging and electrophysiological guidance. J Neurosurg 2000; 92: 615–625. https://doi.org/10.3171/jns.2000.92.4.0615.
- 33Temperli P, Ghika J, Villemure J-G, et al. How do parkinsonian signs return after discontinuation of subthalamic DBS? Neurology 2003; 60: 78–81. https://doi.org/10.1212/WNL.60.1.78.
- 34Hauser RA, Holford NHGG. Quantitative description of loss of clinical benefit following withdrawal of levodopa-carbidopa and bromocriptine in early Parkinson's disease. Mov Disord 2002; 17: 961–968. https://doi.org/10.1002/mds.10226.
- 35Vitek JL, Patriat R, Ingham L, et al. Lead location as a determinant of motor benefit in subthalamic nucleus deep brain stimulation for Parkinson's disease. Front Neurosci 2022; 16: 1–11. https://doi.org/10.3389/fnins.2022.1010253.
- 36Wodarg F, Herzog J, Reese R, et al. Stimulation site within the MRI-defined STN predicts postoperative motor outcome. Mov Disord 2012; 27: 874–879. https://doi.org/10.1002/mds.25006.
- 37Neudorfer C, Butenko K, Oxenford S, et al. Lead-DBS v3 . 0 : mapping deep brain stimulation effects to local anatomy and global networks. Neuroimage. Published online January 2023; 268:119862. https://doi.org/10.1016/j.neuroimage.2023.119862.
- 38Trager MHM, Koop MMMMM, Velisar A, et al. Subthalamic beta oscillations are attenuated after withdrawal of chronic high frequency neurostimulation in Parkinson's disease. Neurobiol Dis. 2016; 96: 22–30. https://doi.org/10.1016/j.nbd.2016.08.003.
- 39Chen Y, Gong C, Tian Y, et al. Neuromodulation effects of deep brain stimulation on beta rhythm: a longitudinal local field potential study. Brain Stimul. 2020; 13: 1784–1792. https://doi.org/10.1016/j.brs.2020.09.027.
- 40Oswal A, Cao C, Yeh CH, et al. Neural signatures of hyperdirect pathway activity in Parkinson's disease. Nat Commun 2021; 12: 1–14. https://doi.org/10.1038/s41467-021-25366-0.
- 41Horn A, Ewert S, Alho EJL, et al. Teaching NeuroImages: In vivo visualization of Edinger comb and Wilson pencils. Neurology 2019; 92: e1663–e1664. https://doi.org/10.1212/WNL.0000000000007252.
- 42Fischer DL, Sortwell CE. BDNF provides many routes toward STN DBS-mediated disease modification. Mov Disord 2019; 34: 22–34. https://doi.org/10.1002/mds.27535.
- 43Rodriguez-rojas R, Pineda-pardo JA, Mañez-miro J, et al. Functional topography of the human subthalamic nucleus: Relevance for subthalamotomy in parkinson's disease. 2022; 37: 279–290. https://doi.org/10.1002/mds.28862.
10.1002/mds.28862 Google Scholar
- 44Akkal D, Dum RP, Strick PL. Supplementary motor area and presupplementary motor area: targets of basal ganglia and cerebellar output. J Neurosci 2007; 27: 10659–10673. https://doi.org/10.1523/JNEUROSCI.3134-07.2007.
- 45Horn A. The impact of modern-day neuroimaging on the field of deep brain stimulation. Curr Opin Neurol 2019; 32: 511–520. https://doi.org/10.1097/WCO.0000000000000679.
- 46Petersen MV, Lund TE, Sunde N, et al. Probabilistic versus deterministic tractography for delineation of the cortico-subthalamic hyperdirect pathway in patients with Parkinson disease selected for deep brain stimulation. J Neurosurg 2017; 126: 1657–1668. https://doi.org/10.3171/2016.4.JNS1624.
- 47Jakab A, Werner B, Piccirelli M, et al. Feasibility of diffusion tractography for the reconstruction of intra-thalamic and cerebello-thalamic targets for functional neurosurgery: a multi-vendor pilot study in four subjects. Front Neuroanat 2016; 10: 1–15. https://doi.org/10.3389/fnana.2016.00076.
- 48Wang Q, Akram H, Muthuraman M, et al. Normative vs. patient-specific brain connectivity in deep brain stimulation. Neuroimage 2021; 224:117307. https://doi.org/10.1016/j.neuroimage.2020.117307.
- 49Ewert S, Horn A, Finkel F, et al. Optimization and comparative evaluation of nonlinear deformation algorithms for atlas-based segmentation of DBS target nuclei. Neuroimage 2019; 184: 586–598. https://doi.org/10.1016/j.neuroimage.2018.09.061.
- 50Lofredi R, Auernig CG, Ewert S, et al. Interrater reliability of deep brain stimulation electrode localizations. Neuroimage 2022; 262:119552. https://doi.org/10.1016/j.neuroimage.2022.119552.
- 51Finder SG, Bliton MJ, Gill CE, et al. Potential subjects’ responses to an ethics questionnaire in a phase I study of deep brain stimulation in early Parkinson's disease. J Clin Ethics 2012; 23: 207–216.
- 52Edlow BL, Mareyam A, Horn A, et al. 7 tesla MRI of the ex vivo human brain at 100 micron resolution. Sci Data 2019; 6: 1–10. https://doi.org/10.1038/s41597-019-0254-8.
Citing Literature
