Pedunculopontine arousal system physiology - Deep brain stimulation (DBS)

Abstract

This review describes the wake/sleep symptoms present in Parkinson׳s disease, and the role of the pedunculopontine nucleus in these symptoms. The physiology of PPN cells is important not only because it is a major element of the reticular activating system, but also because it is a novel target for deep brain stimulation in the treatment of gait and postural deficits in Parkinson׳s disease. A greater understanding of the physiology of the target nuclei within the brainstem and basal ganglia, amassed over the past decades, has enabled increasingly better patient outcomes from deep brain stimulation for movement disorders.

Keywords: Basal forebrain; Calcium channels; DBS, deep brain stimulation; EEG, electroencephalogram; Gamma band activity; LC, locus coeruleus; Lateral hypothalamus; Orexin; PD, Parkinson׳s disease; PGO, ponto-geniculo-occipital; PPN, pedunculopontine nucleus; RAS, reticular activating system; REM, rapid eye movement; SN, substantia nigra; STN, subthalamic nucleus; SubCD, subcoeruleus nucleus dorsalis; Tuberomammillary.

Fig. 1

The P50 potential in PD. Left. Paired click stimuli were delivered at three interstimulus intervals (ISI), 250 ms, 500 ms, and 1000 ms, so that a recovery curve could be plotted. Age- and gender-matched control subjects (black squares) showed ~20%, 30%, and 60% habituation of the second response, respectively. PD patients at stage 3 (red circles) showed ~30%, 50%, and 75% habituation, correspondingly, and were not different from controls. Stage 4 patients showed ~50%, 75%, and 80% correspondingly, and differed from controls at the 250 msec ISI. Stage 5 patients showed decreased habituation at ~73%, 76%, and 95%, correspondingly. Stage 5 patients differed significantly from control subjects at the 250 ms (**p<0.01), and 500 ms (*p<0.05) ISIs (Data from [32]). Right. PD patients recorded before bilateral pallidotomy (inverted red triangles) showed habituation at ~60%, 75%, and 80%, respectively for the three ISIs. After pallidotomy (blue circles), the same patients showed ~35%, 35%, and 60%, respectively. The percent habituation differed significantly between the post- and pre-surgery results at the 250 ms and 500 ms ISIs (**p<0.01), and were not different from control subjects (black squares) (Data from [33]).

Fig. 2

Manifestation of gamma oscillations in PPN neurons requires current ramps instead of current steps. Left. Patch clamp recordings from a PPN neuron in the presence of synaptic blockers and TTX to record intrinsic membrane properties. Application of current steps could not maintain the membrane potential at highly depolarized levels, preventing beta/gamma oscillations mediated by high threshold calcium channels to be manifested. Right. Application of current ramps slowly depolarized the membrane potential until reaching the threshold of the calcium channels mediating the oscillations. The window of activation for this cell was in the −30 mV (black record) to −20 mV (gray record) (Data from [42]).

Fig. 3

Short latency arousal following RAS stimulation compared to long latency after basal forebrain or hypothalamus stimulation. Sagittal diagram of the rodent brain shows the locations of the basal forebrain (BF), lateral hypothalamus (LH), locus coeruleus (LC), pedunculopontine nucleus (PPN), and thalamus (TH). Stimulation of the LC showed a 1–2 s latency to waking, while stimulation of the mesencephalic reticular formation near the PPN showed a similar latency. However, stimulation of the LH exhibited a 20+ s latency, while stimulation of the BF showed a 15 s latency. Inhibition of the LC showed that stimulation of the LH was ineffective, suggesting that LH orexin neurons must activate the RAS in order to have an effect on waking (Data from [44]).