Pedunculopontine nucleus: a new target for deep brain stimulation for akinesia

Abstract

This issue of Neuroreport will, we believe, be a landmark publication in the treatment of Parkinson’s disease and other causes of akinesia. Although continuous electrical stimulation of the thalamus, subthalamic nucleus or internal globus pallidus using deep brain stimulating electrodes with the accompanying controller and battery implanted subcutaneously can alleviate the Parkinsonian dyskinesias that often emerge after several years of dopaminergic therapy [1,2], stimulating these areas usually fails to alleviate the gait freezing, locomotor hesitancy and postural instability that are so disabling [3]. This failure is a source of great frustration for clinicians, carers and utterly disabling for patients. In this issue of Neuroreport, two groups, one from Rome [4] and one from Bristol, UK [5], report their experiences of deep brain stimulation of a new target in the brainstem, the pedunculopontine nucleus (PPN), which has been studied extensively in monkeys [6–8]. The paper by Mazzone et al. [4] in this issue shows that PPN stimulation is safe and that it is accompanied by ‘feelings of well-being’. On the operating table, they made semi-microelectrode recordings from the PPN during stimulation of the subthalamic nucleus and they recorded finger tapping during PPN stimulation. They had chosen to approach the PPN fairly obliquely. But since the PPN region is elongated in shape, this angled approach may not have been ideal and may explain why Mazzone et al. failed to detect significant changes in the PPN recordings on stimulating the STN. Nevertheless, they found a group of neurons there with a low firing frequency of 10 Hz. This is the frequency that best drives the PPN cholinergic neurons in animal experiments, and it was similar to that which Mazzone et al. [4] found the patients liked best, suggesting that driving these putatively cholinergic neurons yielded beneficial effects. They also found that PPN stimulation slightly improved the patient’s rate of finger tapping. It is not surprising that these effects of stimulation on active and passive movements of the hand were small, because primate experiments had shown that the main function of the PPN is to control the postural and locomotor axial, rather than distal, movements. Unfortunately, the group from Rome did not record effects on posture or gait, impairment of which were the symptoms for which the patients had been selected. The study of two patients reported by Gill et al. [5] in this issue is perhaps of even more value to the clinical community. So far, the follow-up has been relatively short, but the great reduction in akinesia, loss of gait freezing and improvement in postural stability are precisely what the monkey experiments predicted. Interestingly, Nandi et al. [8] were able to induce tremor in monkeys by strong stimulation in the PPN, whereas Gill et al. [5] were unable to do so, probably because current spread from the PPN to the superior cerebellar peduncle is less likely in the larger human brain. Gill et al. [5] also provide a valuable breakdown of the patients’ Unified Parkinson’s Disease Rating Scale scores; these show that, unlike for subthalamic nucleus or internal globus pallidus stimulation, even the frequency of falls was significantly reduced, whereas, as in the monkey, effects on movements of the distal extremities were not seen. A significant drop in the patient’s drug requirements was also observed. This accords with personal observations (submitted for publication) that PPN stimulation in monkeys not only substitutes for missing dopaminergic function probably via its ascending connections to the basal ganglia, but it can also bypass dopaminergic function, probably via its descending connections to the brainstem, cerebellar and spinal axial motor centres. Thus, the report by Gill et al. [5] provides valuable information that will allow neurosurgeons to target and implant deep brain stimulators in this structure. Their technique, however, does not allow recording intraoperatively or postoperatively, but such recordings will be crucially important in the future to understand the mechanisms of alleviation. We congratulate both the Rome and Bristol groups for translating the animal experiments on the PPN to the clinic so promptly and successfully. This new target offers the hope of alleviating the symptoms of Parkinsonian patients for whom currently there is no effective treatment, even by deep brain stimulation. In theory, even patients with multiple system atrophy or progressive supranuclear palsy could benefit – indeed, any patient with intractable locomotor and postural akinesia. In addition, given the very low stimulation frequencies required to drive the PPN neurons, found by both groups and again predicted from the monkey experiments [6] the battery life of the pacemaker will be significantly extended; this will greatly improve the cost effectiveness of deep brain stimulation for Parkinson’s disease. The rapid translation of monkey experiments in the laboratory to the alleviation of human suffering in the clinic COMMENTARY NEUROREPORT