Objective Deep brain stimulation (DBS) near the pedunculopontine nucleus (PPN) has been posited to improve medication-intractable gait and balance problems in patients with Parkinson’s disease. However, clinical studies evaluating this DBS target have not demonstrated consistent therapeutic effects, with several studies reporting the emergence of paresthesia and oculomotor side effects. The spatial and pathway-specific extent to which brainstem regions are modulated during PPN-DBS is not well understood. Approach Here, we describe two computational models that estimate the direct effects of DBS in the PPN region for human and translational non-human primate (NHP) studies. The three-dimensional models were constructed from segmented histological images from each species, multi-compartment neuron models, and inhomogeneous finite element models of the voltage distribution in the brainstem during DBS. Main Results The computational models predicted that: 1) the majority of PPN neurons are activated with −3V monopolar cathodic stimulation; 2) surgical targeting errors of as little as 1 mm in both species decrement activation selectivity; 3) specifically, monopolar stimulation in caudal, medial, or anterior PPN activates a significant proportion of the superior cerebellar peduncle (up to 60% in the human model and 90% in the NHP model at -3V); 4) monopolar stimulation in rostral, lateral, or anterior PPN activates a large percentage of medial lemniscus fibers (up to 33% in the human model and 40% in the NHP model at −3V); and, 5) the current clinical cylindrical electrode design is suboptimal for isolating the modulatory effects to PPN neurons. Significance We show that a DBS lead design with radially-segmented electrodes may yield improved functional outcome for PPN-DBS.
Disabling motor signs of Parkinson's Disease including akinesia, bradykinesia, tremor, and muscle rigidity are typically quantified by clinicians using the Unified Parkinson's Disease Rating Scale (UPDRS). These subjective assessments, while useful, often vary among clinicians, making it challenging to evaluate medication and deep brain stimulation (DBS) therapies in multi-center trials. In this study, two designs for a multijoint rigidity-testing device were developed to enable objective, quantitative measures of rigidity. The investigator passively manipulated the subject's joints while stabilizing the appendage distal to the joint with two opposing force transducers, providing a measurement of differential force during the movement. These forces were synchronized to the joint angle, measured by a motion capture camera system. Here, we show feasibility data for detecting changes in muscle rigidity in a parkinsonian non-human primate treated with Sinemet, Globus Pallidus internal (GPi) DBS and/or subthalamic nucleus (STN) DBS.For design 1, the device was tested on six joints: elbow, wrist, shoulder, hip, knee and ankle, and in three states: MPTP, DBS stimulation, and drug therapy. Device 1 was effectively able to quantify rigidity and determine changes in rigidity states among all joints except elbow (p<0.05). For design 2, the device was tested on only the shoulder abduction/adduction and was tested in three states: MPTP, DBS stimulation, and post-DBS stimulation. Design 2 was effectively able to quantify changes in rigidity as well (p<0.05). Ergonomics and durability were considered in the evaluation of the devices.While each device showed promising results, future iterations will also need to address several limitations of the current devices. The eventual goal of this rigidity testing device would be to use it in the clinic to assist neurologists in titrating medication levels and DBS parameters.
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