Pedunculopontine Nucleus Area as a Target for Deep Brain Stimulation

Deep Brain Stimulation of the Pedunculopontine Nucleus

Non-human primate studies have shown that both blocking GABA-ergic inhibition with bicuculline or direct electrical stimulation of the pedunculopontine nucleus at low frequencies (10–30 Hz), reliably increased motor activity. Instead, high frequency stimulation decreased movement, which is consistent with the idea that parkinsonian akinesia is, in part, caused by over-inhibition of the pedunculopontine nucleus by descending afferents from the basal ganglia. Electrical stimulation of the pedunculopontine nucleus at low frequencies is thought to be effective by disinhibition or by driving the inhibited cholinergic and glutamatergic neurons (Nandi et al., 2002; Jenkinson et al., 2004).

Clinical studies have shown that both unilateral and bilateral deep brain stimulation of the pedunculopontine nucleus at low frequency (20–25 Hz) have a beneficial effect on gait in Parkinson's disease and probably less so in patients with progressive supranuclear palsy (Mazzone et al., 2009). This is in line with previous studies that have found that high frequency stimulation of the MPTP-treated monkey pedunculopontine nucleus deep brain stimulation with 100 Hz produced adverse effects, whereas 2.5, 5 and 10 Hz with a pulse width of 120 ms enhanced movement (Jenkinson et al., 2004). A recent study, which used frequencies of 5, 20, 50, 70 and 130 Hz with a pulse width of 60 ms for chronic stimulation, showed improvement of falls in patients with Parkinson's disease at 50–70 Hz stimulation of the pedunculopontine nucleus (Moro et al., 2010). Interestingly, a recent rodent study of deep brain stimulation in the pedunculopontine nucleus has shown that both low (25 Hz) and high frequency (130 Hz) stimulation in the 6-hydroxydopamine rat model of Parkinson's disease improved the time of descent latency in the pole test and total distance travelled in the open field (Rauch et al., 2010). Therefore, both clinical and animal studies indicate that the issue of the optimal frequency and pulse width remains to be determined.

There is great controversy, however, whether the optimal site for stimulation is situated in the pedunculopontine nucleus or adjacent areas. For a number of reasons, including individual variability regarding brain anatomy and variations among the brainstem atlases, variations in target determination are evident. Reliance on atlas-based localization of the pedunculopontine nucleus might be expected to lead to anatomical targeting errors in a number of patients. The simultaneous implications of a systematic approach of using several atlases linked to multimodal neuroimaging techniques could be validated, which would lead to more reliable and reproducible surgical planning (Zrinzo and Zrinzo, 2008; Zrinzo et al., 2008). Also, spiking characteristics of different zones in the pedunculopontine nucleus, cuneiform or subcuneiform might be useful to further delineate the final site for chronic stimulation (Piallat et al., 2009; Shimamoto et al., 2010).

Since the pedunculopontine nucleus is partially damaged in patients with Parkinson's disease it remains arbitrary how the optimal site for deep brain stimulation would be determined. As outlined above, the pedunculopontine nucleus has close proximity to the cuneiform and laterodorsal tegmental nucleus, which contain cholinergic, glutamatergic, GABA-ergic and substance P populations of neurons, and which also have afferent and efferent connections to the basal ganglia. The stimulating contact may possibly affect these adjacent regions to the pedunculopontine nucleus. This is especially likely since the various neuronal populations of this brainstem region partly overlap.

A clinical study in patients with Parkinson's disease has shown the best effects on gait with active contacts located slightly posterior to the pedunculopontine nucleus, i.e. in the cuneiform and subcuneiform nuclei (Ferraye et al., 2010). In addition, the same group showed that imagination of gait results in increased tonic firing of subcuneiform neurons (Piallat et al., 2009). As noted above, in rats, cats and monkeys, similar findings were thought to correspond to the cuneiform (Shik et al., 1966; Eidelberg et al., 1981; Garacia-Rill et al., 1983; Coles et al., 1989). Additionally, it has been shown that the combination of pedunculopontine nucleus stimulation with either subthalamic nucleus or globus pallidus internus may have superior effects than stimulation of either region alone (Mazzone et al., 2009; Schrader et al., 2010).

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