Pallidothalamic tract activation predicts suppression of stimulation-induced dyskinesias in a case study of Parkinson’s disease

Abstract

One of the potential side-effects of deep brain stimulation (DBS) in the subthalamic nucleus (STN) in individuals with Parkinson’s disease is dyskinesia which cannot be relieved by reducing the dosage of levodopa [[1]Limousin P. Pollak P. Hoffmann D. Benazzouz A. Perret J.E. Benabid A.-L. Abnormal involuntary movements induced by subthalamic nucleus stimulation in parkinsonian patients.Mov Disord. 1996; 11: 231-235https://doi.org/10.1002/mds.870110303Crossref PubMed Scopus (149) Google Scholar]. Previous studies reported that stimulation in the area dorsal to STN arrests stimulation-induced dyskinesia [[2]Herzog J. Pinsker M. Wasner M. et al.Stimulation of subthalamic fibre tracts reduces dyskinesias in STN-DBS.Mov Disord. 2007; 22: 679-684https://doi.org/10.1002/mds.21387Crossref PubMed Scopus (49) Google Scholar,[3]Aquino C.C. Duffley G. Hedges D.M. et al.Interleaved deep brain stimulation for dyskinesia management in Parkinson’s disease.Mov Disord. 2019; 34: 1722-1727https://doi.org/10.1002/mds.27839Crossref PubMed Scopus (9) Google Scholar] and can also reduce levodopa-induced dyskinesia [[4]Nishikawa Y. Kobayashi K. Oshima H. et al.Direct relief of levodopa-induced dyskinesia by stimulation in the area above the subthalamic nucleus in a patient with Parkinson’s disease.Neurol Med Chir (Tokyo). 2010; 50: 257-259https://doi.org/10.2176/nmc.50.257Crossref PubMed Scopus (8) Google Scholar,[5]Alterman R.L. Shils J.L. Gudesblatt M. Tagliati M. Immediate and sustained relief of levodopa-induced dyskinesias after dorsal relocation of a deep brain stimulation lead.FOC. 2004; 17: 39-42https://doi.org/10.3171/foc.2004.17.1.6Crossref Google Scholar]. This region dorsal to STN contains a rich collection of ascending and descending fiber pathways including axons from cells in the globus pallidus internus (GPi) that project through the lenticular fasciculus and thalamic fasciculus en route to the thalamus and brainstem. Stimulation of the GPi has been shown to limit levodopa-induced dyskinesias [[6]Yelnik J. Damier P. Bejjani B.P. et al.Functional mapping of the human globus pallidus: contrasting effect of stimulation in the internal and external pallidum in Parkinson’s disease.Neuroscience. 2000; 101: 77-87https://doi.org/10.1016/S0306-4522(00)00364-XCrossref PubMed Scopus (83) Google Scholar] and stimulation of GPi axonal projections has been hypothesized to underlie the ability to control stimulation-induced dyskinesias with DBS in the STN region. Here, we describe the case of a 76 year old male with tremor predominant Parkinson’s disease with symptom onset at age 63 and who was implanted with a Medtronic 3389 DBS lead (Minneapolis, MN, USA) in the left STN for medication-refractory tremor. Levodopa equivalent daily dose at the time of surgery was 700mg. The initial programming of the patient off-medication, resulted in disabling dyskinesia in the contralateral limbs during L STN stimulation (C+ e1- 2V or e0+ e1- 2.5V, frequency: 125 Hz; pulse width: 60 μs; see Fig. 1B), which could be arrested by interleaving stimulation with the most proximal contact on the DBS lead (see accompanying video). To further investigate this novel form of stimulation, we developed a patient-specific computational model using high-field anatomical imaging data set (7 T, 0.4 × 0.4 × 1 mm), diffusion tensor imaging (DTI, 1.25 × 1.25 × 1.25 mm), and post-operative CT imaging. Finite element modeling was combined with multi-compartment biophysical neuron models of the STN and axons of passage to estimate activation of neuronal pathways in and around the STN [[7]Miocinovic S. Parent M. Butson C.R. et al.Computational analysis of subthalamic nucleus and lenticular fasciculus activation during therapeutic deep brain stimulation.J Neurophysiol. 2006; 96: 1569-1580https://doi.org/10.1152/jn.00305.2006Crossref PubMed Scopus (215) Google Scholar,[8]Peña E. Zhang S. Patriat R. et al.Multi-objective particle swarm optimization for postoperative deep brain stimulation targeting of subthalamic nucleus pathways.J Neural Eng. 2018; 15 (066020)https://doi.org/10.1088/1741-2552/aae12fCrossref Scopus (16) Google Scholar] (Fig. 1A). The modeled pathways included the STN efferents parcellated into limbic, motor and associative regions [[9]Plantinga B.R. Temel Y. Duchin Y. et al.Individualized parcellation of the subthalamic nucleus in patients with Parkinson’s disease with 7T MRI.Neuroimage. 2018; 168: 403-411https://doi.org/10.1016/j.neuroimage.2016.09.023Crossref PubMed Scopus (49) Google Scholar]; pallidothalamic tract; cortico-spinal tract of internal capsule (IC); and the cortico-subthalamic tract (hyperdirect pathway, HDP). The activation profile for each pathway was evaluated in the context of clinically effective versus ineffective stimulation on tremor (the primary motor symptom) and suppression of stimulation-induced dyskinesia. Axonal activation within a pathway was defined by the electrical stimulus pulse train generating phase-locked action potentials within the modeled axon. We quantified the model-generated activation profiles for each of the seven neural pathways across monopolar stimulation settings (−1 to -5V) (Fig. 1B). Activation of these neural pathways depended on the location of each electrode contact relative to STN and the surrounding fiber pathways. For example, the pallidothalamic pathway showed more pronounced activation for contact e3, even at low stimulus amplitudes (e.g. -2V), and minimal activation for the other three contacts, even at higher stimulus amplitudes (e.g. -5V). The motor STN pathway showed more robust activation at low stimulus amplitudes (e.g. -2V) through contact e1, whereas higher stimulus amplitudes (e.g. -5V) resulted in fairly consistent activation percentages across all contacts. Comparing these two monopolar configurations (e1 and e3), the models indicated that monopolar configurations could differentially affect the pallidothalamic pathway and motor STN pathway (Fig. 1C). However, activating both pathways robustly (>50% activation) at relatively low stimulus amplitudes, which avoided activation of any of the fibers in internal capsule, was not feasible with monopolar stimulation through a single electrode. To further understand how pathway activation related to clinical outcomes, we compared activation profiles of each pathway with clinical improvement in tremor with DBS. Sigmoidal curves were fit to each activation plot, and only the motor STN pathway significantly correlated with improvement in tremor (R2 = 0.69) (Fig. 1D). In this case, limited improvement in tremor was found for motor STN activation below 30%, and beyond 40% activation, tremor was strongly suppressed. The results suggest that there is a critical population of neurons in the motor STN to modulate to achieve robust tremor control and this phenomenon can be modeled with a sigmoidal function. The challenge with improving tremor with stimulation through contact e1 was the development of stimulation-induced dyskinesia. Stimulation through contact e3, on the other hand, did not result in stimulation-induced dyskinesia, but there was not sufficient pathway activation to achieve robust tremor control. In this case study, we report the use of a novel interleaved stimulation approach between contact e1 and contact e3 in which both tremor and stimulation-induced dyskinesia were controlled (Fig. 1E). For interleaved stimulation at the clinical settings, the patient-specific models showed strong activation (∼58%) of both the motor STN and the pallidothalamic pathway. Dyskinesias are characterized by hyperkinetic movements and have been shown to be suppressed by stimulation of the posteroventral GPi [[6]Yelnik J. Damier P. Bejjani B.P. et al.Functional mapping of the human globus pallidus: contrasting effect of stimulation in the internal and external pallidum in Parkinson’s disease.Neuroscience. 2000; 101: 77-87https://doi.org/10.1016/S0306-4522(00)00364-XCrossref PubMed Scopus (83) Google Scholar]. Our pathway models reinforce this concept that targeting the pallidothalamic pathway can be an important clinical tool to manage dyskinesia with STN-DBS. It is worth mentioning that other pathways in the dorsal region [[3]Aquino C.C. Duffley G. Hedges D.M. et al.Interleaved deep brain stimulation for dyskinesia management in Parkinson’s disease.Mov Disord. 2019; 34: 1722-1727https://doi.org/10.1002/mds.27839Crossref PubMed Scopus (9) Google Scholar], such as ascending dopaminergic, serotonergic, and noradrenergic pathways from the brainstem, not modeled explicitly in this study may be involved as well in the clinical outcomes reported here. The results also suggest that positioning at least one electrode contact dorsal to the STN provides an opportunity to use interleaved stimulation to control dyskinesias should they arise. While patient-specific models with explicit anatomical representations of individual pathways within and around DBS targets are challenging to build [[10]Gunalan K. Chaturvedi A. Howell B. et al.Creating and parameterizing patient-specific deep brain stimulation pathway-activation models using the hyperdirect pathway as an example.in: PLoS ONE. vol. 12. 2017e0176132https://doi.org/10.1371/journal.pone.0176132Crossref Scopus (43) Google Scholar], they provide unique opportunities to investigate the relationship between neural pathway activation and unique clinical cases. Mojgan Goftari: Methodology, Formal analysis, Visualization, Writing - original draft, Writing - review & editing. Jiwon Kim: Formal analysis. Elliot Johnson: Writing - original draft, Visualization, Investigation. Remi Patriat: Writing - review & editing. Tara Palnitkar: Formal analysis, Visualization. Noam Harel: Methodology, Writing - review & editing, Visualization, Supervision. Matthew D. Johnson: Conceptualization, Methodology, Formal analysis, Supervision, Writing - original draft, Writing - review & editing, Visualization. Lauren E. Schrock: Conceptualization, Investigation, Writing - original draft, Writing - review & editing, Visualization. NH is a co-founder and shareholder in Surgical Information Sciences, Inc. RP is a consultant for Surgical Information Sciences, Inc. TH is a consultant for Surgical Information Sciences, Inc. LES has served as a consultant for Medtronic and Boston Scientific. This work was supported by the NIH-NINDS with grants: R01-NS094206 and P50-NS098573 . We also thank the Minnesota Supercomputing Institute for the computational resources. https://www.brainstimjrnl.com/cms/asset/be41db57-8685-4b24-b2bf-35533c68ce74/mmc1.mp4Loading ... 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