Targeting the pedunculopontine nucleus in Parkinson's disease: Time to go back to the drawing board

In summary, what we have learned about the PPN and MLR over the past few years undermines the simplistic model that underpins the rationale for PPN DBS. Our understanding of the relevant circuitry remains rudimentary. Further, much of what we know about these circuits is based on studies in rodents and felines. While it is likely that critical features of posture and locomotion control are phylogenetically conserved, additional non-human primate experiments are needed. Even if we understood the relevant motor circuits in detail, the small sizes of these structures, and the considerable heterogeneity of neurons within the PPN and surrounding structures, indicates that conventional DBS is too blunt an instrument to selectively target the relevant neurons. Finally, manipulating sick neurons adds an additional element of uncertainty. In the context of these facts, it is not surprising that the clinical results of PPN DBS are largely unimpressive.1 Technical refinements in conventional DBS targeting or technology are unlikely to overcome these obstacles. While basic research revealed significant obstacles to manipulating mesopontine neuronal populations, it also indicates circuits in this region are important in gait and balance, and likely relevant to PD. It is plausible that cell type specific manipulations in this region with optogenetic or chemogenetic methods might be useful.50 That said, deploying these technologies in well-designed clinical experiments face a number of hurdles, not the least of which is a much firmer grasp of the neural circuitry controlling gait and posture is required. We need also as well to know how this circuitry is disrupted in PD.51 At this point in time, human experimentation with PPN DBS should be reconsidered. Efforts should focus on sorting out precisely how the PPN/MLR and their afferent and efferent connections work, on what dysfunctions are characteristic of PD, and on developing the technologies needed to rectify these dysfunctions in PD patients.

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