Apathy Following Bilateral Subthalamic Deep Brain Stimulation for Parkinson's Disease: The INTREPID Randomized Controlled Trial

INTRODUCTION: Motivational disturbances including apathy have been reported following bilateral subthalamic deep brain stimulation (STN-DBS). Many studies suggest apathy is associated with dopaminergic denervation and can be unmasked by drug withdrawal and by aggressive drug tapering following surgery. Additionally, it is suspected that stimulation of the limbic-associative sub-regions of STN might serve as a catalyst, an independent cause, or possibly act synergistically with dopaminergic medication reduction. METHODS: INTREPID (NCT01839396) is a multi-center, prospective, double-blinded RCT. Participants with advanced Parkinson's disease (PD) received bilateral STN-DBS and completed a neuropsychological battery at screening (prior to DBS) and at follow up (12-months). Apathy was assessed using the Starkstein Apathy Scale (SAS). Demographic and clinical data including age, gender, disease duration, levodopa-equivalent daily dose (LEDD), and imaging correlates of DBS (including location and volume of stimulated tissue) were analyzed. RESULTS: There were a total of 160 subjects evaluated at 1-year following STN-DBS, 44 (27.5%) reported an improvement in apathy scores of at least 5-points, and 7 (4.4%) an improvement >10 points. Eighteen (11.3%) participants had worsening apathy scores >5 points, and 8 (5%) reported worsening >10 points. Aggregation of stimulation field models (SFM) across the cohorts, indicated that worsening of apathy was associated with activation of limbic and associative areas of the STN. CONCLUSIONS: Bilateral STN-DBS in this prospective dataset revealed both improvement and worsening of apathy at 1-year follow-up visits. Further analysis of LEDD, dopamine agonist use, and volume of tissue activation may help us to understand the clinical factors underpinning apathy following DBS. Appropriate counseling preoperatively coupled with post-operative monitoring is important for setting expectations and for employing appropriate treatment when necessary.