Distributed Global Functional Connectivity Networks Predict Responsiveness to L-DOPA and Subthalamic Deep Brain Stimulation

Abstract

Objective: To investigate global resting-state functional connectivity (rsFC) patterns associated with response to L-DOPA and to subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease (PD). Background: Brain circuit dysfunction in PD involves an extensive global network [1-3]. A distinctive basal ganglia rsFC pattern has been linked with the ranked response to L-DOPA [4]. Methods: Nineteen patients underwent 3-Tesla resting-state functional MRI (rsfMRI) in the ON-medication state prior to STN DBS. Improvement in UPDRS-III hemibody scores were assessed following L-DOPA therapy and STN DBS. Global FC was measured between regions-of- interest (ROIs) defined by the Automated Anatomical Labeling (AAL) atlas and the Montreal Neurologic Institute (MNI) PD25 subcortical atlas. Seed- and network-level correlations were made with an FDR-p < 0.005. Tremor dominant (TD) and akinetic-rigid (AR) subgroups were also compared separately. Graph theoretical analysis was performed with an analysis threshold of FDR-p < 0.005; and then looking at the top 15% of edges. Results: Response to L-DOPA and to DBS displayed cerebellar desynchronization with bilateral thalami and synchronization with bilateral ventromedial prefrontal cortices (vmPFC). L-DOPA response was additionally associated with desynchronization between the vmPFC and the fusiform gyrus. Meanwhile, DBS response was associated with more widespread areas, which have been implicated in visuomotor control and planning [5-7][Fig. 1]. No significant differences in rsFC were seen between TD and AR groups. Graph theory analysis revealed that DBS response was inversely related to global efficiency of the thalamus and putamen bilaterally. No significant graph metrics were found relative to L-DOPA response. Conclusions: Response to DBS and to L-DOPA share similar characteristics - particularly in cerebello-thalamo-cortical circuits, including those that play a role in planning, learning, decision-making, and reward-based behavior [8,9]. Preservation of distributed networks involved in visuomotor control and network integration of striatothalamocortical circuits appear to predict DBS response. These findings shed a light on the mechanism of action of DBS and L-DOPA and may help serve as useful treatment response biomarkers.