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The P13 potential is the rodent equivalent of the P50 potential, which is an evoked response recorded at the vertex (Vx) 50 ms following an auditory stimulus in humans. Both the P13 and P50 potentials are only present during waking and rapid eye movement (REM) sleep, and are considered to be measures of level of arousal. The source of the P13 and P50 potentials appears to be the pedunculopontine nucleus (PPN), a brainstem nucleus with indirect ascending projections to the cortex through the intralaminar thalamus, mediating arousal, and descending inhibitory projections to the caudal pontine reticular formation (CPRF), which mediates the auditory startle response (SR). We tested the hypothesis that intracranial microinjection (ICM) of glutamate (GLU) or GLU receptor agonists will increase the activity of PPN neurons, resulting in an increased P13 potential response, and decreased SR due to inhibitory projections from the PPN to the CPRF, in freely moving animals. Cannulae were inserted into the PPN to inject neuroactive agents, screws were inserted into the Vx in order to record the P13 potential, and electrodes inserted into the dorsal nuchal muscle to record electromyograms and SR amplitude. Our results showed that ICM of GLU into the PPN dose-dependently increased the amplitude of the P13 potential and decreased the amplitude of the SR. Similarly, ICM of N-methyl-d-aspartic acid or kainate into the PPN increased the amplitude of the P13 potential. These findings indicate that glutamatergic input to the PPN plays a role in arousal control in vivo, and changes in glutamatergic input, or excitability of PPN neurons, could be implicated in a number of neuropsychiatric disorders with the common symptoms of hyperarousal and REM sleep dysregulation.

Intrinsic, rhythmic subthreshold oscillations have been described in neurons of regions throughout the brain and have been found to influence the timing of action potentials induced by synaptic inputs. Some oscillations are sodium channel-dependent while others are calcium channel-dependent. These oscillations allow neurons to fire coherently at preferred frequencies and represent the main mechanism for maintaining high frequency network activity, especially in the cortex. Because cortical circuits are incapable of maintaining high frequency activity in the gamma range for prolonged periods, those processes dependent on continuous gamma band activity are subserved by subthreshold oscillations. As such, intrinsic oscillations, coupled with synaptic circuits, are essential to prolonged maintenance of such functions as sensory perception and "binding", problem solving, memory, waking, and rapid eye movement (REM) sleep. [ABSTRACT FROM AUTHOR]

The pedunculopontine nucleus (PPN) region has received considerable attention in clinical studies as a target for deep brain stimulation (DBS) in Parkinson disease. These studies have yielded variable results with an overall impression of improvement in falls and freezing in many but not all patients treated. We evaluated the available data on the surgical anatomy and terminology of the PPN region in a companion paper. Here we focus on issues concerning surgical technique, imaging, and early side effects of surgery. The aim of this paper was to gain more insight into the reasoning for choosing specific techniques and to discuss shortcomings of available studies. Our data demonstrate the wide range in almost all fields which were investigated. There are a number of important challenges to be resolved, such as identification of the optimal target, the choice of the surgical approach to optimize electrode placement, the impact on the outcome of specific surgical techniques, the reliability of intraoperative confirmation of the target, and methodological differences in postoperative validation of the electrode position. There is considerable variability both within and across groups, the overall experience with PPN DBS is still limited, and there is a lack of controlled trials. Despite these challenges, the procedure seems to provide benefit to selected patients and appears to be relatively safe. One important limitation in comparing studies from different centers and analyzing outcomes is the great variability in targeting and surgical techniques, as shown in our paper. The challenges we identified will be of relevance when designing future studies to better address several controversial issues. We hope that the data we accumulated may facilitate the development of surgical protocols for PPN DBS. [ABSTRACT FROM AUTHOR]

Several lines of evidence over the last few years have been important in ascertaining that the pedunculopontine nucleus (PPN) region could be considered as a potential target for deep brain stimulation (DBS) to treat freezing and other problems as part of a spectrum of gait disorders in Parkinson disease and other akinetic movement disorders. Since the introduction of PPN DBS, a variety of clinical studies have been published. Most indicate improvements in freezing and falls in patients who are severely affected by these problems. The results across patients, however, have been variable, perhaps reflecting patient selection, heterogeneity in target selection and differences in surgical methodology and stimulation settings. Here we outline both the accumulated knowledge and the domains of uncertainty in surgical anatomy and terminology. Specific topics were assigned to groups of experts, and this work was accumulated and reviewed by the executive committee of the working group. Areas of disagreement were discussed and modified accordingly until a consensus could be reached. We demonstrate that both the anatomy and the functional role of the PPN region need further study. The borders of the PPN and of adjacent nuclei differ when different brainstem atlases and atlas slices are compared. It is difficult to delineate precisely the PPN pars dissipata from the nucleus cuneiformis, as these structures partially overlap. This lack of clarity contributes to the difficulty in targeting and determining the exact localization of the electrodes implanted in patients with akinetic gait disorders. Future clinical studies need to consider these issues. [ABSTRACT FROM AUTHOR]

Our discovery of low-threshold stimulation-induced locomotion in the pedunculopontine nucleus (PPN) led to the clinical use of deep brain stimulation (DBS) for the treatment of disorders such as Parkinson's disease (PD) that manifest gait and postural disorders. Three additional major discoveries on the properties of PPN neurons have opened new areas of research for the treatment of motor and arousal disorders. The description of (a) electrical coupling, (b) intrinsic gamma oscillations, and (c) gene regulation in the PPN has identified a number of novel therapeutic targets and methods for the treatment of a number of neurological and psychiatric disorders. We first delve into the circuit, cellular, intracellular, and molecular organization of the PPN, and then consider the clinical results to date on PPN DBS. This comprehensive review will provide valuable information to explain the network effects of PPN DBS, point to new directions for treatment, and highlight a number of issues related to PPN DBS. [ABSTRACT FROM AUTHOR]

Propofol (2,6-diisopropylphenol) is a widely used anesthetic agent, but its mechanisms of action are poorly understood. In this report, the effects of three dose levels of propofol (5, 7.5, and 10 mg/kg) on the amplitude of the vertex-recorded, sleep state-dependent P13 midlatency evoked potential were investigated. The P13 potential is generated, at least in part, by the ascending cholinergic reticular activating system (RAS). The RAS is known to be affected by anesthetic agents. Intravenous injections of propofol were found to reduce the amplitude of the P13 potential in a dose- and time-dependent manner. At 2 min post-injection, the mean P13 amplitude was suppressed to 40% of its pre-injection level by the lowest dose, but was suppressed to 10% of pre-injection levels by the two higher doses of propofol. The duration of the suppression of mean P13 potential amplitude was also dose-dependent such that complete recovery occurred by 5 min using 5 mg/kg, by 15 min using 7.5 mg/kg and by 30 min using 10 mg/kg of propofol. Using a paired stimulus paradigm, transient effects on habituation of the P13 potential were observed but only after the highest dose. Thus, one of the mechanisms of propofol may be to affect portions of the RAS which modulate the level of arousal. It may only transiently affect higher systems known to modulate the degree of habituation of responses by the RAS (i.e. processes which modulate habituation and may participate in sensory gating and distractibility). [Copyright &y& Elsevier]