Motor and non-motor effects of PPN-DBS in PD patients: Insights from Intra-operative electrophysiology

Three decades of basic research have focused on the multiple functions sub-served by the pedunculopontine nucleus (PPN) in mammals. Yet, far from understood is the impact that lesioning PPN or modulating PPN-fugal pathways have on motor, limbic and/or associative domains. Recently, we have pioneered the low-frequency deep brain stimulation (DBS) of pontine tegmental areas in severely parkinsonian patients, aiming at providing new insights in the knowledge of this puzzling region. Here we show that, under PPN-DBS, significant amelioration of axial and hypokinetic signs occurs (although to a lesser extent than following STN- DBS in the same patients), together with a normalization of the spinal H reflex. Furthermore, PPN-DBS improves REM sleep behaviour disorder and attentive and cognitive executive performances. As a first step to understand the limited motor response to PPN-DBS, systematic intra-operative recordings in STN were performed during PPN-DBS at 25 Hz. Almost each STN cell showed significant and long-lasting changes of the mean firing frequency during PPN stimulation. However, PPN-ON caused two conflicting effects: a dramatic decrease of the ongoing firing in bursting STN neurons and a large excitatory effect in irregular and tonic neurons. If dampening of STN bursting units seems to be in accord with the PPN therapeutic role, the simultaneous excit- atory influence in non-bursting cells might counteract the efficacy on motor signs. As a further step to understand the mechanisms underlying non-motor bene- fits, FDG-PET imaging was routinely performed in different conditions (PPN- OFF, PPN-ON). These investigations might clarify whether PPN-ON influences the subcortico-cortical pathways responsible for learning processes and goal- directed behaviours. Preliminary data confirm the possibility that PPN-DBS affects multiple ascending pathways involving intralaminar thalamic nuclei and the ventral tegmental area.