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 (MLR), 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 (RAS), 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.

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…During later phases of the disease, other signs and symptoms emerge, specifically gait and balance problems, and cognitive impairments. It is widely believed that balance problems are the result of degeneration in the portion of the PPN that belongs to the mesencephalic locomotor region and/or degeneration of cholinergic cell groups [e.g., 90,[133][134][135][136][137][138][139]. Cognitive impairments are likely caused by a combination of factors, including the extension of significant dopamine loss to nonmotor portions of the basal ganglia, and the spread of pathology to prefrontal cortical regions [132].…”

“…This constellation of findings suggests the possibility that the descending basal ganglia projections to the brainstem may play a greater role in the pathophysiology of akinesia/bradykinesia and movement than is commonly assumed. A particular role of the PPN in the axial control of gait and balance, and in abnormalities of these functions in patients with movement disorders, is suggested by the fact that portions of the PPN are part of the brainstem locomotor region [90,137,138], and the finding that PPN neurons in this region degenerate in PD [133][134][135][136].…”

Midbrain circuits that set locomotor speed and gait selection

“…Analogues of MLR have been observed in many vertebrates including fish, rodents, primates and humans 8,9,11,12 but with conflicting results as to its anatomical location. In addition to CnF the more ventrally located pedunculopontine nucleus (PPN) has been implicated.…”

“…In addition to CnF the more ventrally located pedunculopontine nucleus (PPN) has been implicated. Besides being anatomically separated, each of these regions contains neurons with diverse transmitter phenotypes with excitatory long-range projection neurons –that are glutamatergic in CnF and both glutamatergic and cholinergic in PPN– intermingled with local inhibitory interneurons 11,12 . Electrical stimulation or lesion studies are therefore unable to distinguish the contribution from the various intermingled neuronal populations present in these areas 12,13 .…”

Participation of the pedunculopontine tegmental nucleus in arousal-demanding functions

“…The pedunculopontine tegmental nucleus (PPTg), together with the locus coeruleus and the dorsal raphe nucleus, is a major constituent of the reticular activating system (RAS) [1][2][3]. This neuronal system, which originates in the brainstem, was first thought to be involved in the modulation of the wake/sleep cycle.…”