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This issue is dedicated to a potential new target for the treatment of movement disorders, the pedunculopontine tegmental nucleus (PPTg), or, more simply, the pedunculopontine nucleus, that some authors abbreviate as PPN. We provide an overview of the field as an introduction to the general reader, beginning with the clinical experience to date of Mazzone and co-workers in Rome, some basic questions that need to be addressed, and potential future directions required in order to ensure that the potential benefits of this work are realized. [ABSTRACT FROM AUTHOR]

In Parkinson's disease (PD), the effects of deep brain stimulation of the pedunculopontine nucleus (PPTg-DBS) on gait has been object of international debate. Some evidence demonstrated that, in the late swing-early stance phase of gait cycle, a reduced surface electromyographic activation (sEMG) of tibialis anterior (TA) is linked to the striatal dopamine deficiency in PD patients. In the present study we report preliminary results on the effect of PPTg-DBS on electromyographic patterns during gait in individual PD patients. To evaluate the sEMG amplitude of TA, the root mean square (RMS) of the TA burst in late swing-early stance phase (RMS-A) was normalized as a percent of the RMS of the TA burst in late stance-early swing (RMS-B). We studied three male patients in the following conditions: on PPTg-DBS/on l-dopa, on PPTg-DBS/off l-dopa, off PPTg-DBS/on l-dopa, off PPTg-DBS/off l-dopa. For each assessment the UPDRS III was filled in. We observed no difference between on PPTg-DBS/off l-dopa and off PPTg-DBS/off l-dopa in UPDRS III scores. In off PPTg-DBS/off l-dopa, patient A (right implant) showed absence of the right and left RMSA, respectively, in 80% and 83% of gait cycles. Patient B (right implant) showed absence of the right RMS-A in 86% of cycles. RMS-A of the patient C (left implant) was bilaterally normal. In on PPTg- DBS/off l-dopa, no patient showed reduced RMS-A. Although the very low number of subjects we evaluated, our observations suggest that PPTg plays a role in modulating TA activation pattern during the steady state of gait. [ABSTRACT FROM AUTHOR]

In spite of the existence of pedunculopontine tegmental nucleus (PPTg) projections to cerebellar nuclei, their nature and functional role is unknown. These fibers may play a crucial role in postural control and may be involved in the beneficial effects induced by deep-brain stimulation (DBS) of brainstem structures in motor disorders. We investigated the effects of PPTg microstimulation on single-unit activity of dentate, fastigial and interpositus nuclei. The effects of PPTg stimulation were also studied in rats whose PPTg neurons were destroyed by ibotenic acid and subsequently subjected to iontophoretically applied cholinergic antagonists . The main response recorded in cerebellar nuclei was a short-latency (1.5–2 ms) and brief (13–15 ms) orthodromic activation. The dentate nucleus was the most responsive to PPTg stimulation. The destruction of PPTg cells reduced the occurrence of PPTg-evoked activation of dentate neurons, suggesting that the effect was due to stimulation of cell bodies and not due to fibers passing through or close to the PPTg. Application of cholinergic antagonists reduced or eliminated the PPTg-evoked response recorded in the dentate nucleus. The results show that excitation is exerted by the PPTg on the cerebellar nuclei, in particular on the dentate nucleus. Taken together with the reduction of nicotinamide adenine dinucleotide phosphate-diaphorase-positive neurons in lesioned animals, the iontophoretic experiments suggest that the activation of dentate neurons is due to cholinergic fibers. These data help to explain the effects of DBS of the PPTg on axial motor disabilities in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

The pedunculopontine tegmental nucleus (PPTg) is a component of the locomotor mesencephalic area. In recent years it has been considered a new surgical site for deep brain stimulation (DBS) in movement disorders. Here, using objective kinematic and spatio-temporal gait analysis, we report the impact of low frequency (40Hz) unilateral PPTg DBS in ten patients suffering from idiopathic Parkinson's disease with drug-resistant gait and axial disabilities. Patients were studied for gait initiation (GI) and steady-state level walking (LW) under residual drug therapy. In the LW study, a straight walking task was employed. Patients were compared with healthy age-matched controls. The analysis revealed that GI, cadence, stride length and left pelvic tilt range of motion (ROM) improved under stimulation. The duration of the S1 and S2 sub-phases of the anticipatory postural adjustment phase of GI was not affected by stimulation, however a significant improvement was observed in the S1 sub-phase in both the backward shift of centre of pressure and peak velocity. Speed during the swing phase, step width, stance duration, right pelvic tilt ROM phase, right and left hip flexion-extension ROM, and right and left knee ROM were not modified. Overall, the results show that unilateral PPTg DBS may affect GI and specific spatio-temporal and kinematic parameters during unconstrained walking on a straight trajectory, thus providing further support to the importance of the PPTg in the modulation of gait in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

The nucleus tegmenti pedunculopontine (PPTg) is a new target for deep brain stimulation (DBS) in Parkinson's disease (PD), in particular for ameliorating postural abnormalities and gait disturbances. The objective of the study is to describe the pre-operative planning, the surgical procedures and results of the DBS of PPTg in humans. Thirteen patients were considered. The surgical approach evolved from the traditional 'indirect' method based on stereotactic ventriculography (5 patients) to a more recent 'direct' method, based on both a digital elaboration of axial stereotactic CT scan and on the 'direct' visual 3D representation of the PPTg (8 patients). No major complication occurred. The direct approach allowed to eliminate the major sources of variability caused by the use of the traditional stereotactic approach. The DBS of PPTg induced a significant amelioration of the following clinical symptoms: gait disturbances, freezing on, speech and arising from the chair. These symptoms are usually not improved by levodopa treatment. The implantation of PPTg proved safe and effective in the treatment of levodopa resistant PD patients. The classic determination of stereotactic coordinates, through a proportional system based on ventriculography, utilising as landmark the CA-CP line and the top of the thalamus, and stereotactic atlases, can hardly be applied to brainstem surgery. The 'direct' method, based on both a digital elaboration of axial stereotactic CT scan and, on the 'direct' visualisation of brainstem borders as well as on the 3D representation of the PPTg, permits a better adaptation to individual anatomic features. [ABSTRACT FROM AUTHOR]

Gait disturbances and akinesia are extremely disabling in advanced Parkinson's disease. It has been suggested that modulation of the activity of the pedunculopontine nucleus (PPN) may be beneficial in the treatment of these symptoms. We report the clinical affects of deep brain stimulation (DBS) in the PPN and subthalamic nucleus (STN). Six patients with unsatisfactory pharmacological control of axial signs such as gait and postural stability underwent bilateral implantation of DBS electrodes in the STN and PPN. Clinical effects were evaluated 2-6 months after surgery in the OFF- and ON-medication state, with both STN and PPN stimulation ON or OFF, or with only one target being stimulated. Bilateral PPN-DBS at 25 Hz in OFF-medication produced an immediate 45% amelioration of the motor Unified Parkinson's Disease Rating Scale (UPDRS) subscale score, followed by a decline to give a final improvement of 32% in the score after 3-6 months. In contrast, bilateral STN-DBS at 130-185 Hz led to about 54% improvement. PPN-DBS was particularly effective on gait and postural items. In ON-medication state, the association of STN and PPN-DBS provided a significant further improvement when compared to the specific benefit mediated by the activation of either single target. Moreover, the combined DBS of both targets promoted a substantial amelioration in the performance of daily living activities. These findings indicate that, in patients with advanced Parkinson's disease, PPN-DBS associated with standard STN-DBS may be useful in improving gait and in optimizing the dopamine-mediated ON-state, particularly in those whose response to STN only DBS has deteriorated over time. This combination of targets may also prove useful in extra-pyramidal disorders, such as progressive supranuclear palsy, for which treatments are currently elusive. [ABSTRACT FROM AUTHOR]

Summary. Extracellular electrophysiological recordings of neurons of the parafascicular nucleus of the thalamus were done in normal rats and in rats bearing lesions of either the cerebellar nuclei or the entopeduncular nucleus to investigate the functional control of the pedunculopontine nucleus on the parafascicular nucleus. A total of 97 neurons were recorded in the parafascicular nucleus in intact rats, 83 in rats bearing a chronic electrolytic lesion of the ipsilateral deep cerebellar nuclei, and 69 in rats bearing an ibotenate lesion of the ipsilateral entopeduncular nucleus. Lesions of the cerebellar nuclei or the entopeduncular nucleus were made to evaluate the participation of cerebellothalamic fibers or of polysynaptic basal ganglia circuits in the responses recorded in parafascicular neurons following electrical microstimulation of the ipsilateral pedunculopontine nucleus. Two types of excitation and one type of inhibition were the main responses observed in neurons of the parafascicular nucleus following stimulation of the pedunculopontine nucleus. The first type of excitation, observed in 49.5% of neurons recorded in normal rats, had an onset of 1.8 ± 0.6 ms, lasted 9.2 ± 0.8 ms and was able to follow high frequency stimulation over 300 Hz. The second type of excitation, observed in a smaller percentage of neurons recorded (3.1%), was a long-latency (8.3 ± 0.7 ms) activation lasting 19.0 ± 4.5 ms. It did not follow stimulation frequencies higher than 50–100 Hz. The inhibitory response was observed in 17.5% of the neurons recorded. The latency of this inhibition was 4.5 ± 1.8 ms and the duration 41.9 ± 6.8 ms. In rats bearing a lesion of the deep cerebellar nuclei or of the entopeduncular nucleus, the short-latency activation was still present in 24.1% and 31.9% of neurons recorded, respectively. However, the occurrence of the long-latency excitation rats bearing lesions of either the cerebellum or the entopeduncular nucleus increased to 12.1% and to 17.4%, respectively, while the occurrence of the inhibition rose to 22.9% and to 28.9%. These results show that an excitatory influence on the parafascicular nucleus is exerted by the pedunculopontine nucleus irrespectively of the presence of cerebellofugal fibers. This influence appears to be also independent from the integrity of basal ganglia circuits having a relay at the level of the entopeduncular nucleus. However, the variety of responses recorded suggests that the influences of the pedunculopontine nucleus on the parafascicular nucleus are by far more complex than those exerted on its basal ganglia targets such as the substantia nigra. The results are discussed according to a model of functioning of pedunculopontine fibers directed to thalamic and basal ganglia nuclei. [ABSTRACT FROM AUTHOR]

The interest in the pedunculopontine tegmental nucleus (PPTg), a structure located in the brainstem at the level of the pontomesencephalic junction, has greatly increased in recent years because it is involved in the regulation of physiological functions that fail in Parkinson's disease and because it is a promising target for deep brain stimulation in movement disorders. The PPTg is highly interconnected with the main basal ganglia nuclei and relays basal ganglia activity to thalamic and brainstem nuclei and to spinal effectors. In this review, we address the functional role of the main PPTg outputs directed to the basal ganglia, thalamus, cerebellum and spinal cord. Together, the data that we discuss show that the PPTg may influence thalamocortical activity and spinal motoneuron excitability through its ascending and descending output fibers, respectively. Cerebellar nuclei may also relay signals from the PPTg to thalamic and brainstem nuclei. In addition to participating in motor functions, the PPTg participates in arousal, attention, action selection and reward mechanisms. Finally, we discuss the possibility that the PPTg may be involved in excitotoxic degeneration of the dopaminergic neurons of the substantia nigra through the glutamatergic monosynaptic input that it provides to these neurons. • The pedunculopontine tegmental nucleus is not a mere interface between the basal ganglia and spinal cord • It has an active role in sensorimotor control and higher functions of the brain • Its continuous stimulation may improve motor disabilities in Parkinson's Disease • Its neurons may participate in neurodegenerative mechanisms [ABSTRACT FROM AUTHOR]