During implantation of deep-brain stimulation (DBS) electrodes in the target structure, neurosurgeons and neurologists commonly observe a "microlesion effect" (MLE), which occurs well before initiating subthalamic DBS. This phenomenon typically leads to a transitory improvement of motor symptoms of patients suffering from Parkinson's disease (PD). Mechanisms behind MLE remain poorly understood. In this work, we exploited the notion of ranking to assess spontaneous brain activity in PD patients examined by resting-state functional magnetic resonance imaging in response to penetration of DBS electrodes in the subthalamic nucleus. In particular, we employed a hypothesis-free method, eigenvector centrality (EC), to reveal motor-communication-hubs of the highest rank and their reorganization following the surgery; providing a unique opportunity to evaluate the direct impact of disrupting the PD motor circuitry in vivo without prior assumptions. Penetration of electrodes was associated with increased EC of functional connectivity in the brainstem. Changes in connectivity were quantitatively related to motor improvement, which further emphasizes the clinical importance of the functional integrity of the brainstem. Surprisingly, MLE and DBS were associated with anatomically different EC maps despite their similar clinical benefit on motor functions. The DBS solely caused an increase in connectivity of the left premotor region suggesting separate pathophysiological mechanisms of both interventions. While the DBS acts at the cortical level suggesting compensatory activation of less affected motor regions, the MLE affects more fundamental circuitry as the dysfunctional brainstem predominates in the beginning of PD. These findings invigorate the overlooked brainstem perspective in the understanding of PD and support the current trend towards its early diagnosis.
Keywords: BOLD, blood-oxygenation-level dependent; Brainstem; DBS, deep-brain stimulation; Deep-brain stimulation; EC, eigenvector centrality; FDG-PET, fluorodeoxyglucose positron emission tomography; FDR, false discovery rate; FWE, family-wise error; GP, globus pallidus; ICA, independent component analysis; MLE, microlesion effect; MNI, Montreal Neurological Institute; Microlesion effect; PD, Parkinson's disease; PPN, pedunculopontine nucleus; Parkinson's disease; Resting-state fMRI; SD, standard deviation; STN, subthalamic nucleus; Subthalamic nucleus; UPDRS-III, motor part of the Unified Parkinson's Disease Rating Scale.; fMRI, functional magnetic resonance imaging; rm-ANOVA, repeated measures analysis of variance; rs-fMRI, resting-state fMRI.