Structural Connectivity of the Basal Ganglia from Patient-Individual Tractography Is Key for Understanding the Effects of Deep Brain Stimulation in Parkinson's Disease

Abstract

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.

Keywords: Deep brain stimulation; Parkinson’s disease; Structural connectivity; Tractography.

Fig. 1.

Schematic of the functional neuroanatomy of the cortico-basal ganglia-thalamo-cortical motor loop. Some connections are omitted for the sake of simplicity.

Fig. 2.

Scatter plot of pre- vs. postoperative rigidity score. The black dashed line is the result of linear regression of the displayed points, showing the expected STN-DBS effect. Patients whose postoperative score is below the prediction line are considered good responders (blue circles), while patients whose score is above the predicted one are considered bad responders (red circles).

Fig. 3.

Examples of patient-individual fibre density map of connections between the clinical VTA’s and the cortex (left) and the mean fibre density of the cortical connections of the VTAs filtered from whole-brain tractography in the total cohort in template space (right). S1, primary somatosensory cortex; M1, primary motor cortex; SMA, supplementary motor area; pre-SMA, pre-supplementary motor area; PMd, dorsal premotor cortex; PMv, ventral premotor cortex.

Fig. 4.

Pathway reconstructions in a representative patient. On the left, the involved ROIs are shown. On the other panels, reconstructed streamlines in each pathway (blue: unaffected by DBS, red: modulated by DBS) are shown. ROIs: cortex – green (involved in HDP); putamen – orange; GPe – pink; GPi – blue; STN – cyan; thalamus – purple; VTA – yellow.

Fig. 5.

Streamline counts of structural connections between the STN and cortical regions and basal ganglia nodes.

Fig. 6.

Percentage of fibres modulated by STN-DBS for each pathway.

Fig. 7.

Scatterplots of the proportion of fibres modulated by STN-DBS and the percentage improvement in UPDRS-III score for the most significantly correlated pathways.