Targeted Pathway Activation for PosturalInstability and Gait Disorder in Parkinson'sDisease

Project Summary and Abstract Parkinson's disease (PD) symptoms of postural instability and gait disorder (PIGD) cause profound disability and are inadequately treated by current therapies. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and Globus Pallidus (GP) is effective for PIGD, but not nearly as much as for other PD symptoms e.g. bradykinesia and rigidity. Standard DBS optimization relies on assessing changes in symptoms each time stimulation changes, a very time consuming process. PIGD changes slowly in response to changes in stimulation. Hence, DBS is normally optimized to quicker- responding symptoms, which may be why DBS works better for symptoms other than PIGD. The goal of DBS optimization is to affect neural target structures which best ameliorate symptoms. Different target structures may ameliorate different symptoms. While bradykinesia and rigidity are thought to respond to stimulation of the subthalamopallidal projection, PIGD is thought to involve other structures, especially pedunculopontine nucleus (PPN). PPN afferents and efferents, passing through or near STN & GP may therefore be more effective stimulation targets for PIGD. New directional DBS electrodes, coupled with high field strength MRI imaging and patient-specific computational models, now enable more selective targeting of these pathways. We hypothesize that targeting the ascending PPN efferent pathway will increase the effectiveness of DBS on PIGD, whereas targeting the descending pallidofugal pathway, by inhibiting PPN, will decrease its effectiveness for PIGD. We will compare effects on gait, postural instability, bradykinesia, and rigidity, of DBS targeting pedunculopallidal and pallidopeduncular pathways, directly, as well as subthalamopallidal pathway directly, pallidosubthalamic pathway directly, and pallidopeduncular pathway indirectly (by targeting inhibitory afferents to GP pars interna GPi). Preoperative 7 Tesla structural and diffusion-weighted MRI scans and postoperative high-resolution CT scans will determine electrode location and orientation, relative to nuclei and fiber tracts. Patient-specific models from these imaging datasets will estimate percent activation of each fiber tract, and a novel particle swarm optimization will design stimulation settings maximizing the difference in activation between pathways being compared. Aims 1 (STN) & 2 (GP) compare settings in a single- session, within-subjects experimental design. Aim 3 compares settings with much longer wash- in/ out intervals, and will also collect data between laboratory testing sessions using measures of functional status and quality of life. This project will comprehensively investigate how DBS can be tailored on a patient-specific basis to treat disabling symptoms of PIGD.