Comparatively high excitability of myelinated fibers suggests that they represent a major mediator of deep brain stimulation effects. Such effects can be modeled using different levels of abstraction, ranging from simple electric field estimates to complex multicompartment axon models. In this study, we explore three approaches to estimate axonal activation: electric field magnitudes, electric field projections and (probabilistic) pathway activation modeling. Our aim is to describe these approaches and also illustrate their relevance. For that, we apply them to a clinical dataset of 15 Parkinson's disease patients, who were stimulated in the subthalamic nucleus in bipolar mode. To make these approaches accessible for the community, necessary modeling and statistical processing was implemented in the openly available Lead DBS toolbox.

JR has received speaker honoraria from Medtronic outside of this work. AAK reports a relationship with Medtronic that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. AAK reports a relationship with Boston Scientific Corporation that includes: speaking and lecture fees and travel reimbursement. AAK reports a relationship with Ipsen Pharma that includes: speaking and lecture fees and travel reimbursement. AAK reports a relationship with Teva that includes: speaking and lecture fees and travel reimbursement. AH reports lecture fees for Boston Scientific and is a consultant for FxNeuromodulation and Abbott. KB, BAF, NL, TD, GY, ZGY, ZJ declare no competing interests.

AAK is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Project-ID 424778381 - TRR 295 and under Germany's Excellence Strategy - EXC 2049 - 390688087 (Project Neurocure - BrainLab) and is supported by the Lundbeck Foundation as part of the collaborative project grant "Adaptive and precise targeting of cortex-basal ganglia circuits in Parkinson's Disease" (Grant Nr. R336-2020-1035). AH is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, 424778381 - TRR 295), Deutsches Zentrum fur 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).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of Charité - Universitätsmedizin Berlin gave ethical approval for this work (master vote EA2/186/18). Ethics committee of Beijing Tiantan hospital gave ethical approval for this work (KY2022-006-02).

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The code necessary to reproduce the findings of the study is available at https://github.com/netstim/leaddbs.git The raw data are not publicly available due to patient privacy restrictions, but can be requested from the authors within the scope of a data sharing agreement.