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New Deep Brain Stimulation Algorithm May Help Personalize Parkinson’s Disease Treatment

7 minute read
Brain circuits associated with symptom improvements of tremor (green), bradykinesia (blue), rigidity (red) and axial symptoms (yellow) following deep brain stimulation to the subthalamic nucleus (orange). The pallidum is shown in purple. The backdrop shows a sagittal slice of the BigBrain dataset. Image credit: Nanditha Rajamani

Researchers from Mass General Brigham identified therapeutic targets that may optimize symptom-specific treatment for Parkinson’s disease.

Deep brain stimulation (DBS) has shown promise as a treatment for some symptoms of Parkinson’s disease (PD). However, not all symptoms improve equally well with DBS. A better understanding of how different sites of electrical stimulation impact the wide range of motor symptoms associated with PD could help finetune treatment. By studying PD patients at five different centers treated with DBS, investigators from Mass General Brigham created an “atlas” that mapped four major symptoms of PD onto different regions of the brain. Based on these findings, the team created an algorithm capable of generating personalized, symptom-specific DBS treatment plans, which they preliminarily tested in five patients. Findings, published in Nature Communications, demonstrate the algorithm’s potential to improve patients’ symptoms beyond standard-of-care approaches.

“There is already strong evidence of improved quality of life for PD patients treated with DBS, but currently we still use a ‘one-size-fits-all’ approach to treatment,” said senior author Andreas Horn, MD, PhD, a Mass General Brigham neurologist who holds titles at the Center for Brain Circuit Therapeutics in the Department of Neurology at Brigham and Women’s Hospital and the Center for Neurotechnology and Neurorecovery at Massachusetts General Hospital. “The techniques we have developed will help us readily tailor DBS to what each patient specifically needs and improve DBS even further.”

The researchers from Mass General Brigham studied a total of 237 patients with PD who were treated with DBS to identify tracts associated with four major PD symptoms: tremor (uncontrolled movement), bradykinesia (slow movement), rigidity (freezing), and axial symptoms (such as gait and posture irregularity or instability). With software developed by Horn’s team, the researchers pinpointed the precise location of DBS electrodes in each patient and created a common map of the circuits associated with patients’ symptom improvement. Tremor was shown to improve with stimulation of tracts connected to the primary motor cortex and cerebellum, while bradykinesia was associated with the supplementary motor cortex. Rigidity was shown to improve with stimulation of the premotor cortex.

Zooming into the dysfunctome of the human brain. Left: Brain circuits that may become dysfunctional in brain disorders such as dystonia (yellow), Tourette’s Syndrome (blue), Parkinson’s Disease (green) and obsessive compulsive disorder (red) were recently described by Mass General Brigham researchers (Hollunder et al.). Zooming into the circuit involved in Parkinson’s disease, the new study now segregates the circuit based on specific symptoms (see legend). Image credit: Nanditha Rajamani

Axial symptoms, which have not received extensive study in relation to DBS, improved with stimulation of tracts connected to the supplementary motor cortex and brainstem. This finding may be especially important given that axial symptoms, such as gait or postural stability problems, typically do not respond well to DBS and existing dopaminergic therapies, such as levodopa.

Based on their findings, the investigators created Cleartune, an algorithm that suggests optimal stimulation parameters for DBS stimulation. The researchers applied Cleartune to inform treatment for five PD patients in Germany undergoing DBS. In four of the five patients, Cleartune settings led to greater improvements in PD symptoms than standard-of-care protocols. The fifth patient showed comparable improvements with Cleartune versus standard treatments.

The researchers are continuing to refine personalized, symptom-specific treatment for PD and other diseases, such as OCD, in partnership with Mass General Brigham researchers awarded major National Institutes of Health funding to map the brain’s circuitry more completely using advanced imaging technologies.

“This was an interdisciplinary effort to create the most precise atlas of symptom-specific pathways that we could,” said first and corresponding author Nanditha Rajamani, PhD, of Mass General Brigham. “We went a long way to use anatomical information from many different sources and worked with highly skilled neuroanatomists to produce and validate this research. Going forward, this approach can be a framework for improving DBS treatments for other disorders as well.”

Additional Mass General Brigham co-authors include Helen Friedrich (BWH), Konstantin Butenko (BWH), Till Dembek (BWH), Michael D. Fox (BWH, MGH), Clemens Neudorfer (BWH, MGH).

Other authors include Florian Lange, Pavel Navratil, Patricia Zvarova, Barbara Hollunder, Rob M. A. de Bie, Vincent J. J. Odekerken, Jens Volkmann, Xin Xu, Zhipei Ling, Chen Yao, Petra Ritter, Wolf-Julian Neumann, Georgios P. Skandalakis, Spyridon Komaitis, Aristotelis Kalyvas, Christos Koutsarnakis, George Stranjalis, Michael Barbe, Vanessa Milanese, Andrea A. Kühn, Erik Middlebrooks, Ningfei Li, and Martin Reich.

Disclosures: Rajamani, Horn, and Barabara Hollunder and serve as inventors on a patent application by Charité – University Medicine Berlin that covers multitract fiber filtering and the cleartune algorithm introduced in this work. The application was submitted on July 21, 2023, with the patent office of Luxembourg (application #LU103178). Horn reports lecture fees from Boston Scientific, Inc., and is a consultant for FxNeuromodulation and Abbott, Inc., unrelated to present work. A complete list of disclosures is included in the publication.

Funding: The researchers acknowledge support of funding from the Q8 German Research Foundation (DFG, Deutsche Forschungsgemeinschaft, 424778381) and the Open Access Publication Fund of Charité – Universitätsmedizin Berlin. Horn was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, 424778381 – TRR 295), Deutsches Zentrum für Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND), the National Institutes of Health (R01 13478451, 1R01NS127892-01, 2R01 MH113929 & UM1NS132358) as well as the New Venture Fund (FFOR Seed Grant). Complete funding information is included in the publication.

Paper cited: Rajamani, N et al. “Deep brain stimulation of symptom-specific networks in Parkinson’s disease” Nature Communications DOI: 10.1038/s41467-024-48731-1

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