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Objective: To investigate the effects on the blink reflex (BR) of single stimuli applied to the pedunculopontine tegmental nucleus (PPTg)., Methods: The BR was evoked by stimulating the supraorbital nerve (SON) in fifteen patients suffering from idiopathic Parkinson's disease (PD) who had electrodes monolaterally or bilaterally implanted in the PPTg for deep brain stimulation (DBS). Single stimuli were delivered to the PPTg through externalized electrode connection wires 3-4 days following PPTg implantation., Results: PPTg stimuli increased the latency and reduced duration, amplitude and area of the R2 component of the BR in comparison to the response recorded in the absence of PPTg stimulation. These effects were independent of the side of SON stimulation and were stable for interstimulus interval (ISI) between PPTg prepulse and SON stimulus from 0 to 110 ms. The PPTg-induced prepulse inhibition of the BR was bilaterally present in the brainstem. The R1 component was unaffected., Conclusions: The prepulse inhibition of the R2 component may be modulated by the PPTg., Significance: These findings suggest that abnormalities of BR occurring in PD may be ascribed to a reduction of basal ganglia-mediated inhibition of brainstem excitability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Tourette syndrome is a rare neuropsychiatric disorder affecting the cortico-striato-thalamo-cortical system. The disease manifests in childhood with tics and various psychiatric comorbidities. Cases of refractory Tourette syndrome are valuable candidates for functional neurosurgery. The thalamic centromedian-parafascicular complex is an experimental target that shows a promising role in Tourette syndrome deep brain stimulation, due to pathophysiologic evidences. We have shown on a long term follow-up, that thalamic deep brain stimulation, targeted on the centromedian-parafascicular complex, could modulate motor (i.e. tics) symptoms and owns a putative effect on various psychiatric aspects. Non-responding psychiatric symptoms could be due to the aberrant developmental environment of young Tourette patients more than disease itself. Centromedian-parafascicular complex is intriguingly embedded in motor, associative and limbic pathways and should be further investigated in his role for neuromodulation of human movement and behavior., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The region of the pedunculopontine tegmental nucleus (PPTg) has been proposed as a novel target for deep brain stimulation (DBS) to treat levodopa resistant symptoms in motor disorders. Recently, the anatomical organization of the brainstem has been revised and four new distinct structures have been represented in the ventrolateral pontine tegmentum area in which the PPTg was previously identified. Given this anatomical reassessment, and considering the increasing of our experience, in this paper we revisit the value of DBS applied to that area. The reappraisal of clinical outcomes in the light of this revisitation may also help to understand the consequences of DBS applied to structures located in the ventrolateral pontine tegmentum, apart from the PPTg. The implantation of 39 leads in 32 patients suffering from Parkinson's disease (PD, 27 patients) and progressive supranuclear palsy (PSP, four patients) allowed us to reach two major conclusions. The first is that the results of the advancement of our technique in brainstem DBS matches the revision of brainstem anatomy. The second is that anatomical and functional aspects of our findings may help to explain how DBS acts when applied in the brainstem and to identify the differences when it is applied either in the brainstem or in the subthalamic nucleus. Finally, in this paper we discuss how the loss of neurons in brainstem nuclei occurring in both PD and PSP, the results of intraoperative recording of somatosensory evoked potentials, and the improvement of postural control during DBS point toward the potential role of ascending sensory pathways and/or other structures in mediating the effects of DBS applied in the ventrolateral pontine tegmentum region.

The pedunculopontine tegmental nucleus (PPTg) relays basal ganglia signals to the thalamus, lower brainstem and spinal cord. Using the 6-hydroxydopamine (6-OHDA) rat model of parkinsonism, we investigated whether deep brain stimulation (DBS) of the PPTg (40 Hz, 60 μs, 200-400 μA) may influence the preparative and executive phases in a conditioned behavioural task, and the motor asymmetries induced by apomorphine. In the conditioned task, rats had to press two levers according to a fixed delay paradigm. The 6-OHDA lesion was placed in the right medial forebrain bundle, i.e. contralaterally to the preferred forepaw used by rats to press levers in the adopted task. The stimulating electrode was implanted in the right PPTg, i.e. contralateral to left side, which was expected to be most affected. The lesion significantly reduced correct responses from 63.4% to 16.6%. PPTg-DBS effects were episodic; however, when rats successfully performed in the task (18.9%), reaction time (468.8 ± 36.5 ms) was significantly increased (589.9 ± 45.9 ms), but not improved by PPTg-DBS (646.7 ± 33.8 ms). Movement time was significantly increased following the lesion (649.2 ± 42.6 ms vs. 810.9 ± 53.0 ms), but significantly reduced by PPTg-DBS (820.4 ± 39.4 ms) compared to sham PPTg-DBS (979.8 ± 47.6 ms). In a second group of lesioned rats, rotations induced by apomorphine were significantly reduced by PPTg-DBS compared to sham PPTg-DBS (12.2 ± 0.6 vs. 9.5 ± 0.4 mean turns/min). Thus, it appears that specific aspects of motor deficits in 6-OHDA-lesioned rats may be modulated by PPTg-DBS., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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 (40 Hz) 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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The pedunculopontine tegmental nucleus (PPTg) is a novel target for deep brain stimulation (DBS) in movement disorders., Objective: To clarify the relationships between the individual anatomic variations of the brainstem, the site in which the PPTg DBS is applied, and the clinical outcome in a relatively large number of patients affected by Parkinson disease or progressive supranuclear palsy., Methods: Magnetic resonance images have been used to evaluate brainstem anatomy and the relationships between lead position and specific brainstem landmarks. All data were matched on atlas representations of the PPTg and were correlated with Unified Parkinson Disease Rating Scale III (UPDRS III), subitems 27 to 30 of UPDRS III and the Hoehn and Yahr evaluations., Results: A high variance of brainstem parameters was evident, affecting the relationships between the position of the nucleus and lead contacts. According to the contacts giving the best clinical outcome, patients could be distinguished between those who required the use of 2 adjacent contacts and those who required stimulation through 2 nonadjacent contacts. Furthermore, in the former group the target coordinates were more lateral and deeper compared with the latter group., Conclusion: Individual PPTg-DBS planning is required to overcome the inconsistencies linked to the high variability in the brainstem anatomy of patients. The lack of correlations between lead position, contact setup, and clinical outcome indicate that the benefits of PPTg DBS may not be strictly linked to the site of stimulation within the PPTg area, and may not depend upon the neurons still surviving in this region in Parkinson disease or progressive supranuclear palsy.

Background: Jaw movements are severely affected in Parkinson's disease. Deep brain stimulation (DBS) of basal ganglia targets is known to ameliorate oromotor control. In this study, we examined the effects of DBS of the pedunculopontine tegmental nucleus (PPTg) on jaw movements in selected parkinsonian patients., Methods: The effects of low-frequency (25 Hz) stimulation of the PPTg on jaw movements were investigated through electrognathographic analysis in parkinsonian patients who were selected for PPTg stimulation. Changes in jaw velocity and amplitude during voluntary opening and closing movements of the mouth, as well as the maximum frequency of self-paced sequences of opening and closing cycles, were analyzed., Results: Low-frequency stimulation of the PPTg in the OFF-drugs condition significantly improved the opening and closing velocities, vertical amplitude and rhythm of voluntary movements. In some instances, movement parameters during stimulation were within the range of those recorded in healthy controls., Discussion: This is the first study investigating the impact of PPTg DBS on oromotor control in parkinsonian patients. The results show that jaw movements may be restored under stimulation and suggest that the pedunculopontine nucleus may play a key role in controlling oromotor activity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The application of deep brain stimulation (DBS) to the pedunculopontine tegmental nucleus (PPTg) has required profound modifications of classic neurosurgical techniques and of the criteria for evaluation of clinical results. This review analyzes a novel method of targeting the PPTg, based on angio-computerized tomography (angio-CT) scans and the tridimensional reconstruction of nuclei and cerebral vessels, and considers the advantages of applying these methods in comparison to the more traditional approach based on reference points obtained through the evaluation of the bicommessural line. Validation of the results obtained following unilateral PPTg DBS through neurophysiological recordings and objective measurements of functional parameters suggests that the PPTg may be considered as an initial target for the treatment of motor symptoms in selected patients affected by idiopathic Parkinson's disease (PD), which, if required, could be followed by DBS of other target areas. Moreover, on the basis of the observations derived from stimulating the PPTg, the potential utility attributed up to date to intraoperative neurophysiological recordings for identifying neurosurgical targets should be revisited, and the need for changes in the intraoperative management of patients has arisen from the body of evidence accumulated over recent years. The results obtained by different groups following PPTg DBS in parkinsonian patients are not uniform, most likely due to a cautious acceptance of this methodology, the experience progressively acquired, the criteria for patient selection and to subtle differences in target location. Although the role of PPTg in PD and/or in other pathologies remains to be clarified, pursuing the traditional approach on classical basal ganglia targets may limit the perspective of DBS based on multiple implantations.

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.

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.

Subthalamic nucleus single-unit recordings were undertaken before and during pedunculopontine [corrected] nucleus-stimulation at clinically relevant frequency (25 Hz) in six patients with Parkinson's disease. Pedunculopontine [corrected] nucleus stimulation changed the firing activity of almost every subthalamic nucleus cell (44/48) by decreasing the ongoing discharge in bursting subthalamic nucleus neurons (-62.1%) and exciting irregular (+63.2%) and tonic/regular discharges (+20.1%). These conflicting data challenge the definition of pedunculopontine [corrected] nucleus as a new target area for Parkinson's disease. If the modulation of subthalamic nucleus bursting units may corroborate the pedunculopontine [corrected] nucleus therapeutic role, the simultaneous excitatory influence during nonbursty patterns might interfere with a favorable outcome on motor signs. As a result, the implantation of pedunculopontine [corrected] nucleus alone may be hazardous while the association of subthalamic nucleus plus pedunculopontine [corrected] nucleus seems to be reasonable.

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.

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.

The peduncolopontine nucleus modulates locomotor activity and dysfunction in this nucleus may be responsible for the gait and postural impairments seen in Parkinson's disease and other movement disorders. We report the first surgical exploration and implantation of deep brain stimulating electrodes of the peduncolopontine nucleus area in two Parkinson's disease patients to examine the safety and the potential benefit of chronic electrical stimulation at this site. Under local anesthesia, the peduncolopontine nucleus was approached from a coronal burr hole using a trajectory that was 78-80 degrees and 62-64 degrees on the coronal and sagittal planes. Microrecordings helped to identify neurons in peduncolopontine nucleus and the adjacent substantia nigra pars reticulata. Chronic deep brain stimulating electrodes were implanted within the peduncolopontine nucleus in a manner similar to that practiced with deep brain stimulating surgery at other targets. Peduncolopontine nucleus neurons were characterized by small and broad multiunits (230 muV, 2.5 ms, 14.6 Hz). Caudal to this area, neurons firing at higher frequency, approximately 70 Hz, characteristic of nigral neuronal discharges, were encountered, followed by 2 mm of cells similar to those recorded in the dorsal peduncolopontine nucleus area. After deep brain stimulating electrodes implantation, acute intraoperative stimulation (up to 3 V) was performed with two stimulation frequencies in each session. Stimulation at 80 Hz has little discernable effect. On the other hand, stimulation at 10 Hz fostered a subjective feeling of 'well-being' and a time-locked amelioration of the clinical scores. These findings demonstrate that the stereotactic approach of peduncolopontine nucleus is safe. The target may reliably be identified by microrecordings. Low-frequency stimulation may produce acute improvements in motor function.

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 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]