Computational modeling of pedunculopontine nucleus deep brain stimulation

Abstract

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.

Particle swarm optimization for programming deep brain stimulation arrays

“…Axon models consisted of 2 μm diameter fibers with compartments representing nodes of Ranvier, myelin attachment segments, paranode main segments, and internode segments connected through an axial resistance [16]. Axonal membrane compartments were each driven using the extracellular mechanism in NEURON (e_extracellular) [6], [8], [43]. We applied a waveform with a 90 μs cathode-leading phase, 400 μs interphase delay, 3 ms charge-balanced anodic phase, and 135 Hz pulse rate [44].…”

“…With this increase in number and distribution of electrode sites, these so-called DBS arrays (DBSAs) expand the programming options for steering, shifting, and sculpting volumes of neural activation [3], [7]. Such functionality may be especially important when DBS leads are positioned in a brain region with a non-uniform target morphology [8], or when DBS leads are implanted in close proximity to nuclei or fiber pathways that, when stimulated, evoke adverse side effects [3], [5], [6]. …”

Theoretical Optimization of Stimulation Strategies for a Directionally Segmented Deep Brain Stimulation Electrode Array

“…A major improvement to this existing design would be enabling one to direct or steer current both along and around the DBS lead. This feature would be especially useful in cases of off-target DBS implants [5], [6] and for small or complex-shaped brain targets, such as the pedunculopontine nucleus [7], [8] for treating freezing of gait in patients with PD.…”

“…Several designs for high-density DBS arrays (DBSAs) with circumferentially-segmented electrodes have been advanced in recent years through computational studies [5], [8], [9] and in-vivo studies in non-human primates (NHPs) [6] and humans [10], [11], [12]. Here, we modeled DBS leads with 32 oval shaped electrodes arranged in 8 rows of 4 electrodes each, radially separated by 90° [6], [5], [8].…”

“…Here, we modeled DBS leads with 32 oval shaped electrodes arranged in 8 rows of 4 electrodes each, radially separated by 90° [6], [5], [8]. The surface areas of the DBSA electrodes were a fraction of the size of cylindrical electrodes found on commercial leads and have potential for improving the spatial resolution of targeting modulation of neuronal activity within the brain to improve overall therapy.…”