The physiology of the pedunculopontine nucleus: implications for deep brain stimulation

Abstract

This brief review resolves a number of persistent conflicts regarding the location and characteristics of the mesencephalic locomotor region, which has in the past been described as not locomotion-specific and is more likely the pedunculopontine nucleus (PPN). The parameters of stimulation used to elicit changes in posture and locomotion we now know are ideally suited to match the intrinsic membrane properties of PPN neurons. The physiology of these 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 the treatment of gait and postural deficits in Parkinson's disease (PD). The discussion explains many of the effects reported following deep brain stimulation (DBS) of the PPN by different groups and provides guidelines for the determination of long-term assessment and effects of PPN DBS. 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 DBS for movement disorders. Despite these improvements, there remains a great opportunity for further understanding of the mechanisms through which DBS has its effects and for further development of appropriate technology to effect these treatments. We review the scientific basis for one of the newest targets, the PPN, in the treatment of PD and other movement disorders, and address the needs for further investigation.

Figure 1. The human PPN in relation to adjacent structures. Top image

Sagittal sections from a human brain in which cholinergic cells from the PPN and laterodorsal tegmental nuclei were immunocytochemically labeled with choline acetyltransferase antibody, and locus coeruleus and substantia nigra neurons were labeled with tyrosine hydroxylase antibody. Each neuron in each section was rendered as a 100 µM sphere. This view is from the lateral aspect of the pons and midbrain showing at top the fourth ventricle (IV), at bottom the basis pontis, and at the top right, the inferior and superior colliculi (IC, SC). The PPN appears as a cluster of red neurons with the densest collection at the posterior edge, the pars compacta (denoted as a circle). Anterior to the PPN is the subtantia nigra with green cells. More medially and deep in the view are the puprple cells denoting the locus coeruleus and the yellow cells denoting the laterodorsal tegmental nucleus. Bottom image. Sagittal sections from another human brain labeled similarly to the top image. The first section along the midline shows the fourth ventricle dorsally (IV), the basis pontis ventrally, and the inferior and superior colluculi to the left and dorsally (IC, SC). Note the central canal dividing the colliculi from the tegmentum in this section. Neurons of the laterodorsal tegmental nucleus are shown as yellow spheres, and those of the locus coeruleus are again in purple, while PPN cells in red are evident more laterally and deepest in the image with the pars compacta denoted as a circle. Substantia nigra neurons are in green, showing the medial substantia nigra to be well separated from the more dorsal laterodorsal tegmental nucleus and locus coeruleus.

Figure 2. Gamma band activity in whole-cell recorded PPN cells

A. Increasing steps of current (increase of 30 pA per step, each step was 500 ms in duration delivered every 2.5 sec) caused cells to fire action potentials at increasingly higher frequencies. This cell fired maximally at 54 Hz, i.e within gamma band range. B. Graph showing the firing frequency of ten cells at each current step (small bullets) and of the average of the 50 recorded cells (large red bullets, R2 = 0.994). The average maximal firing frequency was at the 180 pA current step, where cells fired at the average rate of 50 ± 16 Hz for all cells. C. Graph showing the firing frequency of each cell at the 180 pA current step, divided according to cell type (black dots). The average firing frequency of each cell type is also shown (red bullets). Type 1 neurons fired significantly faster than type II or III cells, but type II and III neurons did not fire action potentials significantly faster than one another. The average maximal firing frequency for type I, II, and III neurons were: 58 ± 15 Hz, 45 ± 15 Hz, and 46 ± 16 Hz, respectively.

Figure 3. Effects of steps vs ramps in eliciting gamma band oscillations in PPN neurons

A. Current clamp recording of a PPN neuron to which were applied current steps of increasing amplitude (dark blue trace represents the response to lower amplitude square current while light blue represents the response to higher amplitude square current pulses). Note that the membrane potential failed to be maintained and repolarized below the window for high threshold, voltage-dependent calcium channels. B. Recordings in the same neuron but using ramps of increasing amplitude (brown trace represents the response to lower amplitude current ramp while red represents the response to higher amplitude current ramp). Note that the membrane potential could be gradually increased to induce membrane oscillations that could be maintained within the window for activation of high threshold calcium channels (around −20 mV in the soma, but much lower in the dendrites). Further studies showed that these were P/Q-type voltage-dependent calcium channels (Kezunovic et al. 2011).

Figure 4. Localization of calcium channels in the dendrites of PPN neurons

These studies used a ratiometric calcium imaging method designed to detect calcium flux at high speeds (Hyde et al. 2013). A. Records of ramp-elicited calcium oscillations recorded simultaneously with both electrical recording (black record) and high speed fluorescence imaging (red in the soma, blue in one dendrite). The oscillations in the somatic fluorescence recording (red record) closely matched those in the electrical record. The blue dendritic record also followed the electrical record, but with more variation. Note that the electrical and fluorescence changes were eliminated by the addition of Cd²⁺ or a P/Q-type calcium channel blocker (Hyde et al. 2013). B. Cross-correlation of the electrical record (black record) and the somatic fluorescence record (red record). The inset shows a view of calcium flux in the patched neuron. Calibration bar 25 µm.