Left prefrontal connectivity links subthalamic stimulation with depressive symptoms in Parkinson’s disease

Abstract

In Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) for treatment of Parkinson s Disease (PD), there is a paradigm shift away from focal stimulation of target structures toward effects of stimulation on distributed brain networks. While the relationship between modulated networks and motor outcomes has received much attention, network impact of non-motor DBS effects has been less well characterized. In the affective domain, STN DBS improves depressive symptoms in some patients, while it leads to no change or even symptom-worsening in others. Here, we systematically investigate the impact of electrode placement and associated structural connectivity on changes in depressive symptoms following STN-DBS. Depressive symptoms before and 6 to 12 months after STN-DBS surgery were documented in 116 PD patients from three DBS centers (Berlin, Queensland, Cologne). Individual electrode placements were reconstructed based on preoperative and postoperative imaging using LeadDBS software. Applying a finite element approach the volumes of tissue activated (VTA) were estimated and combined with normative connectome data to identify structural connections passing through VTAs. Berlin and Queensland data (N=80) were used for training and crossvalidation to identify a structural connectivity profile that could explain improvement or worsening of depressive symptoms. The Cologne dataset (n=36) served as test-set for which depressive symptom change was predicted. We identified a robust pattern linking structural connectivity to depressive symptoms under STN-DBS. An optimal connectivity map trained on the Berlin cohort could predict changes in depressive symptoms in Queensland patients (R =0.52, p<0.0001) and vice versa (R=0.57, p<0.0001). Furthermore, the joint training-set map predicted changes in depressive symptoms in the independent test-set from Cologne (R=0.36, p=0.012). Crucially, worsening of depressive symptoms was consistently associated with connectivity to left dorsolateral prefrontal areas, the prime target for non-invasive stimulation in depression. In contrast, depressive symptoms improved in patients with less connectivity to the left PFC. Results remained significant when controlling for motor improvement and dopaminergic medication withdrawal. A specific structural connectivity profile implicating a leftlateralized prefrontal to STN network predicts depressive symptoms following STN DBS: fibers linking the STN electrode with left prefrontal areas predicted worsening of depressive symptoms across DBS centers, cohorts and surgeons. Our results suggest that for the left STN DBS lead, placement impacting fibers to left prefrontal areas should be avoided to maximise improvement of depressive symptoms. These findings pave the way toward personalized brain stimulation in which individual connectivity profiles and symptom constellations may determine optimal DBS targeting.