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

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 symptomworsening 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 6-12 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 preand postoperative imaging using Lead-DBS 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 left-lateralized prefrontal–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. All rights reserved. No reuse allowed without permission. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint . http://dx.doi. org/10.1101/665976 doi: bioRxiv preprint first posted online Jun. 10, 2019;