Combined Theta-gamma STN Stimulation for Verbal Fluency in Parkinson Disease

Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is an established, effective, and relatively safe therapeutic option for Parkinson's disease (PD) patients presenting levodopa-related motor complications despite the best medical therapy . Chronic high-frequency (130-180 Hz) stimulation is known to reduce motor fluctuations and dyskinesia, and to improve quality of life and several non-motor symptoms . However, current evidence suggests a long term decline of cognitive performance in PD patients with STN-DBS compared to those without DBS, especially executive function processes including verbal fluency. Preliminary evidence from pilot studies suggested that low frequency theta oscillations (4-10 Hz) within the STN and correlated cortical networks are important in cognition, including verbal fluency, color-word interference, and spatial and episodic memory; cortical structures involved in category verbal fluency encompass not only the prefrontal cortex, but also the hippocampus and related medial temporal structures. There is also evidence that theta STN stimulations lead to a worsening of motor symptoms, compared with no stimulation and therapeutic stimulation (gamma frequency). To date, new DBS systems allow the use of multiple current sources and/or frequency settings at different depths and directions in a single electrode, and then to combine different stimulation frequencies. Considering this, the aim is to evaluate the use of combined high (gamma) and very low (theta) frequency stimulation in a randomized, cross-over, double-blind trial with this principal research questions: 1. Can combined theta-gamma theta frequency STN stimulation improve verbal fluency in PD patients? 2. Can combined theta-gamma frequency STN stimulation improve verbal frequency without worsening cardinal motor symptoms?