INTRODUCTION: In Parkinson's disease (PD) patients, modulation of the fibre tracts of the cortico-basal ganglia-thalamo-cortical loop is the presumed mechanism of action of deep brain stimulation (DBS) of the subthalamic nucleus (STN). Therefore, we explored patient-individual cortical structural connectivity of the volume of tissue activated (VTA), as well as DBS-induced modulation of fibre tracts connecting the STN with cortical and subcortical nodes, and their correlation with therapeutic effects. METHODS: A retrospective cohort of n = 69 PD patients treated with bilateral DBS of the STN was analysed. Clinical response was assessed from the DBS-induced change in the UPDRS-III motor scores (total and symptom-specific sub-scores) under regular medication after a median follow-up of 9.0 (range 2.6-20.2) months. Tractography based on patient-individual diffusion-weighted MRI was employed in two ways. Whole-brain tractography was used to identify the cortical connections of fibres passing the VTAs, and reconstruction of specific white matter pathways of the motor loop connecting the STN with the basal ganglia and cortex was used to identify the proportion of fibres within these pathways which was modulated by STN-DBS. This proportion of pathway modulation was used in a correlative analysis with clinical outcomes. RESULTS: Fibres traversing the VTAs were primarily connected to the supplementary motor area (SMA) and to a lesser degree to the premotor cortex. Within the pathways connecting the STN with the cortical and subcortical nodes, on average 30-40% (range 10-80%) of the fibres were modulated by STN-DBS. This proportion correlated significantly with the percentage change in UPDRS motor score for fibres connecting the STN with the SMA (ρ = 0.28), pre-SMA (ρ = 0.26), ventral and dorsal premotor cortices (ρ = 0.26 and ρ = 0.29, respectively), and the globus pallidus externus (ρ = 0.26) and internus (ρ = 0.29). Also, good clinical responses for both tremor and rigidity were associated with a significantly (p < 0.05) higher proportion of modulated fibres for the same cortico- and sub-cortico-STN connections. CONCLUSION: Patient-individual tractography reveals that, in PD, most of the cortical fibres traversing the VTA are connected to the SMA. In addition, clinical efficacy is related to the proportion of DBS-affected fibres connecting the STN with nodes of both the hyperdirect (cortex-STN) and the indirect pathways (STN-basal ganglia). As such, patient-specific tractography, in particular in the basal ganglia, could be used in a clinical context as a tool to guide therapy.

Cognitive Neuroimaging Unit CEA INSERM Université Paris Saclay NeuroSpin Center Gif sur Yvette France

Department of Cognitive Neuroscience Faculty of Psychology and Neuroscience Maastricht University Maastricht The Netherlands

Department of Electrical and Electronics Engineering National Magnetic Resonance Research Center Bilkent University Ankara Turkey

Department of General Neurosurgery Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague Czechia

Department of Neurology Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Department of Stereotactic and Functional Neurosurgery Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Division of Neurosurgery Department of Surgery Toronto Western Hospital University of Toronto Toronto Ontario Canada

Mental Health and Neuroscience Research Institute Maastricht University Medical Centre Maastricht The Netherlands

Movement Disorders Unit Foch Hospital Université Paris Saclay Suresnes France

Research Department Brain Innovation BV Maastricht The Netherlands

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