What is the therapeutic mechanism of pedunculopontine nucleus stimulation in Parkinson's disease?

Abstract

Pedunculopontine nucleus (PPN) deep brain stimulation (DBS) is an experimental treatment for Parkinson's disease (PD) which offers a fairly circumscribed benefit for gait freezing and perhaps balance impairment. The benefit on gait freezing is variable and typically incomplete, which may reflect that the clinical application is yet to be optimised or reflect a fundamental limitation of the therapeutic mechanism. Thus, a better understanding of the therapeutic mechanism of PPN DBS may guide the further development of this therapy. The available evidence supports that the PPN is underactive in PD due to a combination of both degeneration and excessive inhibition. Low frequency PPN DBS could enhance PPN network activity, perhaps via disinhibition. A clinical implication is that in some PD patients, the PPN may be too degenerate for PPN DBS to work. Reaction time studies report that PPN DBS mediates a very specific benefit on pre-programmed movement. This seems relevant to the pathophysiology of gait freezing, which can be argued to reflect impaired release of pre-programmed adjustments to locomotion. Thus, the benefit of PPN DBS on gait freezing could be akin to that mediated by external cues. Alpha band activity is a prominent finding in local field potential recordings from PPN electrodes in PD patients. Alpha band activity is implicated in the suppression of task irrelevant processes and thus the effective allocation of attention (processing resources). Attentional deficits are prominent in patients with PD and gait freezing and PPN alpha activity has been observed to drop out prior to gait freezing episodes and to increase with levodopa. This raises the hypothesis that PPN DBS could support or emulate PPN alpha activity and consequently enhance the allocation of attention. Although PPN DBS has not been convincingly shown to increase general alertness or attention, it remains possible that PPN DBS may enhance the allocation of processing resources within the motor system, or “motor attention”. For example, this could facilitate the ‘switching’ of motor state between continuation of pattern generated locomotion towards the intervention of pre-programmed adjustments. However, if the downstream consequence of PPN DBS on movement is limited to a circumscribed unblocking of pre-programmed movement, then this may have a similarly circumscribed degree of benefit for gait. If this is the case, then it may be possible to identify patients who may benefit most from PPN DBS. For example, those in whom pre-programmed deficits are the major contributors to gait freezing.