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

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.

Gamma band activity in the RAS-intracellular mechanisms.

Gamma band activity participates in sensory perception, problem solving, and memory. This review considers recent evidence showing that cells in the reticular activating system (RAS) exhibit gamma band activity, and describes the intrinsic membrane properties behind such manifestation. Specifically, we discuss how cells in the mesopontine pedunculopontine nucleus, intralaminar parafascicular nucleus, and pontine SubCoeruleus nucleus dorsalis all fire in the gamma band range when maximally activated, but no higher. The mechanisms involve high-threshold, voltage-dependent P/Q-type calcium channels, or sodium-dependent subthreshold oscillations. Rather than participating in the temporal binding of sensory events as in the cortex, gamma band activity in the RAS may participate in the processes of preconscious awareness and provide the essential stream of information for the formulation of many of our actions. We address three necessary next steps resulting from these discoveries: an intracellular mechanism responsible for maintaining gamma band activity based on persistent G-protein activation, separate intracellular pathways that differentiate between gamma band activity during waking versus during REM sleep, and an intracellular mechanism responsible for the dysregulation in gamma band activity in schizophrenia. These findings open several promising research avenues that have not been thoroughly explored. What are the effects of sleep or REM sleep deprivation on these RAS mechanisms? Are these mechanisms involved in memory processing during waking and/or during REM sleep? Does gamma band processing differ during waking versus REM sleep after sleep or REM sleep deprivation?

AROUSAL FROM SLICES TO HUMANS: Translational studies on sleep-wake control.

Most psychiatric and neurological disorders exhibit sleep disorders, and in some cases presage the disease. Study of the control of sleep and waking has the potential for making a major impact on a number of disorders, making translational neuroscience research on this area critical. One element of the reticular activating system (RAS) is the pedunculopontine nucleus (PPN), which is the cholinergic arm of the RAS, and projects to the thalamus to trigger thalamocortical rhythms and to the brainstem to modulate muscle tone and locomotion. We developed a research program using brainstem slices containing the PPN to tell us about the cellular and molecular organization of this region. In addition, we developed the P13 midlatency auditory evoked potential, which is generated by PPN outputs, preparation in freely moving rats. This allows the study of PPN cellular and molecular mechanisms at the level of the whole animal. We also study the P50 midlatency auditory evoked potential, which is the human equivalent of the rodent P13 potential, allowing us to study processes detected in vitro, confirmed in the whole animal, and tested in humans. This translational research program led to the discovery of a novel mechanism of sleep-wake control, pointing the way to a number of new clinical applications in the development of novel stimulants and anesthetics.