Objective: We aim to monitor the deep brain stimulation (DBS) circuit engagement at single neuron resolution and want to leverage this insight for physiology-driven design of intermittent burst stimulation (ibDBS) in Parkinsons Disease (PD).

Background: DBS of the subthalamic nucleus (STN) provides symptomatic relief in PD. ibDBS that produces cell-specific effects has been shown to outperform conventional forms of DBS in rodents (Spix et al., Science, 2021). In human subjects, delivery of brief high-frequency pulse trains has been suggested to produce prolonged therapeutic effects (Adamchic et al, Mov Disord, 2014). Despite these preclinical and experimental clinical efforts, ibDBS has shown mixed effects in clinical reality. Translation may in part have been halted by the difficulty to probe new DBS paradigms at similar resolution, as single cell readouts are difficult to achieve in human subjects.

Method: We designed a stimulation and dual-site recording strategy during DBS implantation surgery in PD patients levering the unique opportunity to record single cell activity in the intraoperative setting. Continuous and intermittent burst stimulation was applied to the STN while recording evoked resonant neural activity (ERNA) from the STN and ERNA/concurrent action potential (AP) firing from the microtip placed in the Substantia Nigra pars reticulata (SNr).

Results: Continuous high frequency stimulation in the STN induced significant, stimulation-intensity and -frequency depended suppression of neuronal firing in the SNr. Intermittent burst stimulation resulted in neuronal inhibition in SNr after individual bursts of stimulation in STN and critically depended on stimulation location and intra-burst stimulation frequency. The return of neuronal firing after stimulation trains informed optimal inter-burst duration to achieve downstream neuronal inhibition. Furthermore, evoked potential signatures showed significant correlations with neuronal inhibition and could be picked up by both STN-macro- and SNr-microcontacts, providing essential prerequisites for the translation from the intraoperative setting to clinical reality.

Conclusion: Our preliminary findings suggest that single-cell readouts of subthalamic DBS at basal ganglia output structures can not only help us gain insight into the single cell mechanism of subthalamic DBS, but may provide critical input for physiology-driven refinement of DBS strategies.

References: Spix TA, Nanivadekar S, Toong N, Kaplow IM, Isett BR, Goksen Y, Pfenning AR, Gittis AH. Population-specific neuromodulation prolongs therapeutic benefits of deep brain stimulation. Science. 2021 Oct 8;374(6564):201-206. doi: 10.1126/science.abi7852. Epub 2021 Oct 7. PMID: 34618556; PMCID: PMC11098594.

Adamchic I, Hauptmann C, Barnikol UB, Pawelczyk N, Popovych O, Barnikol TT, Silchenko A, Volkmann J, Deuschl G, Meissner WG, Maarouf M, Sturm V, Freund HJ, Tass PA. Coordinated reset neuromodulation for Parkinson’s disease: proof-of-concept study. Mov Disord. 2014 Nov;29(13):1679-84. doi: 10.1002/mds.25923. Epub 2014 Jun 28. PMID: 24976001; PMCID: PMC4282372

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MDS Abstracts - https://www.mdsabstracts.org/abstract/towards-intraoperative-physiology-informed-design-of-intermittent-burst-deep-brain-stimulation/