Background: Tractography based on diffusion-weighted magnetic resonance imaging (DWI) models the structural connectivity of the human brain. Deep brain stimulation (DBS) targeting the subthalamic nucleus is an effective treatment for advanced Parkinson's disease, but may induce adverse effects. This study investigated the relationship between structural connectivity patterns of DBS electrodes and stimulation-induced side effects. Materials and Methods: Twenty-one patients with Parkinson's disease treated with bilateral subthalamic DBS were examined. Overall, 168 electrode contacts were categorized as inducing or noninducing depending on their capability for inducing side effects such as motor effects, paresthesia, dysarthria, oculomotor effects, hyperkinesia, and other complications as assessed during the initial programming session. Furthermore, the connectivity of each contact with target regions was evaluated by probabilistic tractography based on DWI. Finally, stimulation sites and structural connectivity patterns of inducing and noninducing contacts were compared. Results: Inducing contacts differed across the various side effects and from those mitigating Parkinson's symptoms. Although contacts showed a largely overlapping spatial distribution within the subthalamic region, they could be distinguished by their connectivity patterns. In particular, inducing contacts were more likely connected with supplementary motor areas (hyperkinesia, dysarthria), frontal cortex (oculomotor), fibers of the internal capsule (paresthesia), and the basal ganglia-thalamo-cortical circuitry (dysarthria). Discussion: Side effects induced by DBS seem to be associated with distinct connectivity patterns. Cerebellar connections are hardly associated with side effects, although they seem relevant for mitigating motor symptoms in Parkinson's disease. A symptom-specific, connectivity-based approach for target planning in DBS may enhance treatment outcomes and reduce adverse effects. Impact statement Tractography based on diffusion-weighted magnetic resonance imaging has become a prominent technique for investigating the connectivity of human brain networks in vivo. However, the relationship between structural connections and brain function is still hardly known. The present study examined the relationship between adverse behavioral effects induced by deep brain stimulation (DBS) and tractography patterns in individual brains. The results suggest that DBS-based side effects depend on the structural connections of electrode contacts rather than their location. Network-based target planning in DBS may improve treatment by avoiding side effects. Moreover, the adopted approach may serve as a paragon for investigating structure/function relationships.

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