Pedunculopontine Nucleus Stimulation Research Articles

Improved control effect of pathological oscillations by using delayed feedback stimulation in neural mass model with pedunculopontine nucleus.

The role of delayed feedback stimulation in the discussion of Parkinson's disease (PD) has recently received increasing attention. Stimulation of pedunculopontine nucleus (PPN) is an emerging treatment for PD. However, the effect of PPN in regulating PD is ignored, and the delayed feedback stimulation algorithm is facing some problems in parameter selection. On the basis of a neural mass model, we established a new network for PPN. Four types of delayed feedback stimulation schemes were designed, such as stimulating subthalamic nucleus (STN) with the local field potentials (LFPs) of STN nucleus, globus pallidus (GPe) with the LFPs of Gpe nucleus, PPN with the LFPs of Gpe nucleus, and STN with the LFPs of PPN nucleus. In this study, we found that all four kinds of delayed feedback schemes are effective, suggesting that the algorithm is simple and more effective in experiments. More specifically, the other three control schemes improved the control performance and reduced the stimulation energy expenditure compared with traditional stimulating STN itself only. PPN stimulation can affect the new network and help to suppress pathological oscillations for each neuron. We hope that our results can gain an insight into the future clinical treatment.

Efficacy of caudal pedunculopontine nucleus stimulation on postural instability and gait disorders in Parkinson’s disease

Gait-related symptoms like postural instability and gait disorders (PIGD) inexorably worsen with Parkinson's disease (PD) deterioration and become refractory to current available medical treatment and deep brain stimulation (DBS) of conventional targets. Pedunculopontine nucleus (PPN) deep brain stimulation (DBS) is a promising method to treat PIGD. This prospective study aimed to clarify the clinical application of PPN-DBS and to explore effects of caudal PPN stimulation on PIGD. Five consecutive PD patients with severe medication-resistant postural instability and gait disorders accepted caudal PPN-DBS. LEAD-DBS toolbox was used to reconstruct and visualize the electrodes based on pre- and postoperative images. Outcomes were assessed with Movement Disorder Society (MDS)-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), gait-specific questionnaires, and objective gait analysis with GAITRite system. MDS-UPDRS subitems 35-38 scores were improved at postoperative 6months (mean, 4.40 vs 11.00; p = 0.0006) and 12months (mean, 5.60 vs 11.00; p = 0.0013) compared with baseline, and scores at 6months were slightly lower than scores at 12months (mean, 4.40 vs 5.60; p = 0.0116). Gait and Falls Questionnaire, New Freezing of Gait Questionnaire, and Falls Questionnaire scores also significantly improved at postoperative 6months and 12months compared with baseline. In addition, cadence, bilateral step length, and bilateral stride length significantly increased when PPN On-stimulation compared with Off-stimulation. This study suggested that caudal PPN low-frequency stimulation improved PIGD for PD patients at the 6- and 12-month period.

Cardiovascular autonomic responses in patients with Parkinson disease to pedunculopontine deep brain stimulation.

Dysautonomia can be a debilitating feature of Parkinson disease (PD). Pedunculopontine nucleus (PPN) stimulation may improve gait disorders in PD, and may also result in changes in autonomic performance. To determine whether pedunculopontine nucleus stimulation improves cardiovascular responses to autonomic challenges of postural tilt and Valsalva manoeuver, eight patients with pedunculopontine nucleus deep brain stimulation were recruited to the study; two were excluded for technical reasons during testing. Participants underwent head up tilt and Valsalva manoeuver with stimulation turned ON and OFF. Continuous blood pressure and ECG waveforms were recorded during these tests. In a single patient, local field potential activity was recorded from the implanted electrode during tilt. The fall in systolic blood pressure after tilt was significantly smaller with stimulation ON (mean - 8.3% versus - 17.2%, p = 0.044). Valsalva ratio increased with stimulation from median 1.15 OFF to 1.20 ON (p = 0.028). Baroreflex sensitivity increased during Valsalva compared to rest with stimulation ON versus OFF (p = 0.028). The increase in baroreflex sensitivity correlated significantly with the mean depth of PPN stimulating electrode contacts. This accounted for 89% of its variance (r = 0.943, p = 0.005). PPN stimulation can modulate the cardiovascular system in patients with PD. In this study, it reduced the postural fall in systolic blood pressure during head-up tilt and improved the cardiovascular response during Valsalva, presumably by altering the neural control of baroreflex activation.

Dynamical role of pedunculopntine nucleus stimulation on controlling Parkinson’s disease

Parkinson’s disease (PD) is considered to be associated with the abnormal activities of the cortex–thalamus and basal ganglia. Besides these nuclei, anatomical evidence indicates that the pedunculopontine nucleus (PPN) also plays a crucial role in the modulation of PD, yet relevant biophysical mechanisms are not completely explained. In this paper, on the basis of a biophysical mean-field model, a new network model for PPN is established. The connection parameters between the PPN and other nuclei are determined from experimental data. Preliminary analysis indicates that although stimulating PPN has little effect on the firing rate of the system, the impact of PPN on the firing pattern is significant. According to the nature of the oscillatory activity in PD and the complexity of PPN control over PD, two kinds of origin of parkinsonian oscillations are studied. The parkinsonian oscillation activities can be controlled and modulated by the direct projection from the PPN to the subthalamic nucleus (STN), and may successfully alleviate akinesia. Moreover, the dynamical bifurcation mechanisms underlying these transitions are analyzed. With the increasing of these parameters, the system produces a supercritical Hopf bifurcation from the unstable equilibrium state to the stable state, but it returns to the unstable state again as the parameters become large enough. More importantly, when a stimulus is added to the PPN, the oscillation can be suppressed at the beginning, but as the stimulation parameter gradually increases, it is excited again. The obtained results can be helpful to understand the PPN stimulation in treating Parkinson patients, and provide a theoretical basis for future clinical studies.

Pedunculopontine and Subthalamic Nucleus Stimulation Effect on Saccades in Parkinson Disease

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been explored as a target to treat axial motor symptoms of advanced Parkinson disease (PD). The aim of this study was to consider relative effects of bilateral subthalamic nucleus (STN) and PPN DBS on both initiation and inhibition of saccades in advanced PD. Five patients with advanced PD performed 2 different oculomotor tasks off stimulation, with bilateral STN DBS, with bilateral PPN DBS, and with simultaneous bilateral STN and PPN DBS. The first task involved visually guided saccades, and the second task involved antisaccades (ASs). Saccadic latency, accuracy, and velocity were recorded for both the visually guided saccade and AS tasks, and prosaccades were measured for the AS task alone. Control subjects included patients with advanced PD without DBS, age-matched healthy subjects, and young healthy subjects (n= 12 in each group). Simultaneous bilateral STN and PPN DBS produced the greatest improvement in mean latencies, velocities, and accuracies for visually guided saccades and ASs compared with DBS off (P < 0.001). Bilateral STN and PPN DBS caused a significant additional improvement compared with STN DBS alone by reducing the number of prosaccades (P < 0.01). It is known that the frontal lobe is involved in saccadic inhibition during AS tasks. Hence, our novel finding of an improvement in the AS task suggests an ascending, frontally mediated effect of PPN DBS. This implies that there may be PPN-to-frontal lobe connections that may partly explain the benefits of PPN DBS in axial motor function.

Balance control systems in Parkinson's disease and the impact of pedunculopontine area stimulation.

Impaired balance is a major contributor to falls and diminished quality of life in Parkinson's disease, yet the pathophysiology is poorly understood. Here, we assessed if patients with Parkinson's disease and severe clinical balance impairment have deficits in the intermittent and continuous control systems proposed to maintain upright stance, and furthermore, whether such deficits are potentially reversible, with the experimental therapy of pedunculopontine nucleus deep brain stimulation. Two subject groups were assessed: (i) 13 patients with Parkinson's disease and severe clinical balance impairment, implanted with pedunculopontine nucleus deep brain stimulators; and (ii) 13 healthy control subjects. Patients were assessed in the OFF medication state and blinded to two conditions; off and on pedunculopontine nucleus stimulation. Postural sway data (deviations in centre of pressure) were collected during quiet stance using posturography. Intermittent control of sway was assessed by calculating the frequency of intermittent switching behaviour (discontinuities), derived using a wavelet-based transformation of the sway time series. Continuous control of sway was assessed with a proportional-integral-derivative (PID) controller model using ballistic reaction time as a measure of feedback delay. Clinical balance impairment was assessed using the 'pull test' to rate postural reflexes and by rating attempts to arise from sitting to standing. Patients with Parkinson's disease demonstrated reduced intermittent switching of postural sway compared with healthy controls. Patients also had abnormal feedback gains in postural sway according to the PID model. Pedunculopontine nucleus stimulation improved intermittent switching of postural sway, feedback gains in the PID model and clinical balance impairment. Clinical balance impairment correlated with intermittent switching of postural sway (rho = - 0.705, P < 0.001) and feedback gains in the PID model (rho = 0.619, P = 0.011). These results suggest that dysfunctional intermittent and continuous control systems may contribute to the pathophysiology of clinical balance impairment in Parkinson's disease. Clinical balance impairment and their related control system deficits are potentially reversible, as demonstrated by their improvement with pedunculopontine nucleus deep brain stimulation.

Effects of pedunculopontine nucleus stimulation on human bladder function.

The pedunculopontine nucleus (PPN) is a deep brain stimulation target for Parkinson's disease (PD). Unilateral PPN stimulation has been described in a previous case report to provoke urinary frequency, urgency and detrusor overactivity, due to probable activation of the pontine micturition center. Our aim was to evaluate the effect of bilateral PPN DBS on urodynamic parameters and to investigate the likely mechanisms using probabilistic tractography. Six male PD subjects with bilateral PPN deep brain stimulators were recruited. Urodynamic bladder filling assessments were carried out with the stimulators ON and OFF. Two subjects also had diffusion-weighted and T1-weighted MRI scans performed and probabilistic tractography was carried out to describe white matter connections with the stimulated area. Five subjects completed urodynamic testing. PPN DBS did not give rise to detrusor overactivity or lower sensory thresholds during bladder filling. However, there was a significant increase in maximal bladder capacity with stimulation: mean bladder volume at maximal capacity was 199 mL (range 103-440) ON stimulation compared with 131 mL (range 39-230) OFF stimulation. Tractography demonstrated extensive connectivity to cortical and subcortical regions, some of which have been implicated in bladder control. Fiber pathways also passed close to the vicinity of the pontine micturition center. Bilateral PPN DBS did not have a detrimental effect on urodynamic filling parameters or produce detrusor overactivity, but did slightly increase maximal capacity. Possible mechanisms include long-range connectivity or local effects at the pontine micturition center.

Deep Brain Stimulation of Pedunculopontine Nucleus for Postural Instability and Gait Disorder After Parkinson Disease: A Meta-Analysis of Individual Patient Data.

Postural instability and gait disorder (PIGD) in Parkinson disease (PD) has been a great challenge in clinical practice because PIGD is closely linked to major morbidity and mortality in PD. Pedunculopontine nucleus (PPN) has been considered as a potential promising target for deep brain stimulation (DBS) in the treatment of PIGD. Ameta-analysis of individual patient data was performed to assess the effects of PPN DBS on PIGD in patients with PD and explore the factors predicting good outcome. According to the study strategy, we searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials, and other sources. After searching the literature, 2 investigators independently screened the literature, assessed the quality of the included trials, and extracted the data. The outcome measures included PIGD, freezing of gait, and falling in PD. Then, individual patient data were incorporated into SPSS software for statistical analyses across series. Six studies reporting individual patient data were included for final analysis. PPN DBS significantly improved PIGD as well as freezing of gait and falling after PD, which was depending on the duration of follow-up and types of outcome measures. In addition, patient age, disease duration, levodopa-equivalent dosage, and the choice of unilateral or bilateral stimulation were similar in groups of patients with PD with or without improvement in PIGD after PPN DBS. Our study provides evidence that PPN DBS may improve PIGD, which should be interpreted with caution and needs further verification before making generalization of our results.

Physiology of freezing of gait.

Freezing of gait (FOG) is a common and debilitating, but largely mysterious, symptom of Parkinson disease. In this review, we will discuss the cerebral substrate of FOG focusing on brain physiology and animal models. Walking is a combination of automatic movement processes, afferent information processing, and intentional adjustments. Thus, normal gait requires a delicate balance between various interacting neuronal systems. To further understand gait control and specifically FOG, we will discuss the basic physiology of gait, animal models of gait disturbance including FOG, alternative etiologies of FOG, and functional magnetic resonance studies investigating FOG. The outcomes of these studies point to a dynamic network of cortical areas such as the supplementary motor area, as well as subcortical areas such as the striatum and the mesencephalic locomotor region including the pedunculopontine nucleus (PPN). Additionally, we will review PPN (area) stimulation as a possible treatment for FOG, and ponder whether PPN stimulation truly is the right step forward. Ann Neurol 2016;80:644-659.

The effect of pedunculopontine nucleus deep brain stimulation on postural sway and vestibular perception.

Background and purposeDeep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) reduces the number of falls in patients with Parkinson's disease (PD). It was hypothesized that enhanced sensory processing contributes to this PPN‐mediated gait improvement.MethodsFour PD patients (and eight matched controls) with implanted bilateral PPN and subthalamic nucleus DBS electrodes were assessed on postural (with/without vision) and vestibular perceptual threshold tasks.ResultsPedunculopontine nucleus ON stimulation (compared to OFF) lowered vestibular perceptual thresholds but there was a disproportionate increase in the normal sway increase on going from light to dark.ConclusionsThe disproportionate increased sway with PPN stimulation in the dark may paradoxically improve balance function since mechanoreceptor signals rapidly adapt to continuous pressure stimulation from postural akinesia. Additionally, the PPN‐mediated vestibular signal enhancement also improves the monitoring of postural sway. Overall, PPN stimulation may improve sensory feedback and hence balance performance.

Modulation of attentional processing by deep brain stimulation of the pedunculopontine nucleus region in patients with parkinsonian disorders.

Low-frequency electrical stimulation of the pedunculopontine nucleus (PPN) is a therapeutic approach aiming to improve motor symptoms such as freezing of gate and postural instability in parkinsonian disorders. Because the PPN is a component of the reticular activating system, we tested whether PPN stimulation directly affects attention and consciousness. Eight patients with parkinsonian disorders and implanted with electrodes in the bilateral PPN underwent computerized assessment of attention. Performance in 3 standard reaction time (RT) tasks was assessed at 5 different stimulation frequencies in 5 consecutive sessions. Stimulation of the PPN at low (8 Hz) and therapeutic (20 Hz) frequencies led to a significant improvement of performance in a simple RT task. Patients' RTs were significantly faster at stimulation frequencies of 8 Hz and 20 Hz relative to no stimulation. Stimulation did not affect patients' performance in more complex attentional tasks. Low-frequent stimulation of PPN improves basal attentional processing in patients with parkinsonian disorders, leading to an improved tonic alertness. As successful performance in this task requires the intrinsic ability to build up and keep a certain level of attention, this might be interpreted as attentional augmentation related to stimulation features. Stimulation had no effect on more complex attentional processing. Our results suggest an influence of the PPN on certain aspects of attention, supporting attentional augmentation as one possible mechanism to improve motor action and gait in patients with parkinsonian disorders.

Low-frequency stimulation of the pedunculopontine nucleus affects gait and the neurotransmitter level in the ventrolateral thalamic nucleus in 6-OHDA Parkinsonian rats

The pedunculopontine nucleus (PPN) is connected to spinal, cerebellar and cerebral motor control structures and can be activated with external electrodes. Intrinsic cholinergic neuronal degeneration in the PPN is associated with postural instabilities and gait disturbances (PIGD) in advanced Parkinson’s disease (PD). Clinical studies have demonstrated that PPN stimulation may improve PIGD. We investigated this claim and the underlying mechanisms using the 6-hydroxydopamine (6-OHDA) hemilesion model of PD. In this study, gait-related parameters, including the base of support (BOS), stride length, and maximum contact area, were analyzed via CatWalk gait analysis following PPN–low frequency stimulation (LFS) of rats with unilateral 6-OHDA lesions. Additionally, neurotransmitter concentrations in the ventrolateral thalamic nucleus (VL) were measured by microdialysis and liquid chromatography–mass spectrometry (LC–MS). Our data revealed that unilateral 6-OHDA lesions of the medial forebrain bundle (MFB) induced significant gait deficits. PPN–LFS significantly improved the BOS (hindlimb) and maximum contact area (impaired forelimb) scores, whereas no other gait parameters were significantly affected. Unilateral 6-OHDA MFB lesions significantly decreased acetylcholine (ACh) and moderately decreased noradrenaline (NA) concentrations in the VL. PPN–LFS mildly reversed the ACh loss in the VL in the lesioned rats but did not alter the NA levels. Taken together, our data indicate that PPN–LFS is useful for treating gait deficits of PD and that these effects are probably mediated by a rebalancing of ACh levels in the PPN–VL pathway. Thus, our findings provide possible insight into the mechanisms underlying PIGD in PD.

Bilateral Pedunculopontine Nucleus Stimulation for Progressive Supranuclear Palsy

The pedunculopontine nucleus (PPN) is a potential target for gait disorders. We report 4 cases of bilateral PPN stimulation in progressive supranuclear palsy (PSP) patients with short-term (6 months) and long-term (18 months) follow-ups. Patients with PSP who had gait disturbances, but were able to walk with or without assistance, were selected. The patients' median age was 64 years and the disease duration 3 years. Bilateral PPN deep brain stimulation (DBS) was performed. The pacemaker was programmed using a bipolar mode and lower frequencies (20-45 Hz). The PSP rating scores (PSPRS) and their gait subscores (No. 25, 26, 27 and 28) along with PSP staging scores were used as primary end points. The total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS III and the 39-item Parkinson's Disease Questionnaire were considered as secondary end points. Video recordings of the gaits were performed before surgery and at the 6- and 18-month follow-ups. These were retrospectively reviewed by a blinded neurologist for the primary end points. At the 6- and 18-month follow-ups, the median change in PSPRS was from 33 (baseline) to 37.5 and 47, respectively. Similarly, the PSP staging changed from 3 to 2.5 and 3.5, item 25 from 1.5 to 2 and 3.5, item 26 from 2.5 to 2 and 3.5, item 27 from 3.5 to 3 and 3.5 and item 28 from 1.5 to 1.5 and 3. Two patients in the study with the PSP-parkinsonism phenotype experienced improvement in their gait until the last follow-up. Bilateral PPN DBS can be safely performed in PSP patients despite mid-brain atrophy.

Pedunculopontine Nucleus Stimulation: Where are We Now and What Needs to be Done to Move the Field Forward?

Falls and gait impairment in Parkinson’s Disease (PD) is a leading cause of morbidity and mortality, significantly impacting quality of life and contributing heavily to disability. Thus far axial symptoms, such as postural instability and gait freezing, have been refractory to current treatment approaches and remain a critical unmet need. There has been increased excitement surrounding the surgical targeting of the pedunculopontine nucleus (PPN) for addressing axial symptoms in PD. The PPN and cuneate nucleus comprise the mesencephalic locomotor region, and electrophysiologic studies in animal models and human imaging studies have revealed a key role for the PPN in gait and postural control, underscoring a potential role for DBS surgery. Previous limited studies of PPN deep brain stimulation (DBS) in treating gait symptoms have had mixed clinical outcomes, likely reflect targeting variability and the inherent challenges of targeting a small brainstem structure that is both anatomically and neurochemically heterogeneous. Diffusion tractography shows promise for more accurate targeting and standardization of results. Due to the limited experience with PPN DBS, several unresolved questions remain about targeting and programing. At present, it is unclear if there is incremental benefit with bilateral versus unilateral targeting of PPN or whether PPN targeting should be performed as an adjunct to one of the more traditional targets. The PPN also modulates non-motor functions including REM sleep, cognition, mood, attention, arousal, and these observations will require long-term monitoring to fully characterize potential side effects and benefits. Surgical targeting of the PPN is feasible and shows promise for addressing axial symptoms in PD but may require further refinements in targeting, improved imaging, and better lead design to fully realize benefits. This review summarizes the current knowledge of PPN as a DBS target and areas that need to be addressed to advance the field.

The effect of low frequency stimulation of the pedunculopontine tegmental nucleus on basal ganglia in a rat model of Parkinson's disease

The pedunculopontine nucleus (PPN) has recently been introduced as an alternative target to the subthalamic nucleus (STN) or globus pallidus internus (GPi) for the treatment of advanced Parkinson's disease with severe and medically intractable axial symptoms such as gait and postural impairment. However, it is little known about how electrical stimulation of the PPN affects control of neuronal activities between the PPN and basal ganglia. We examined how low frequency stimulation of the pedunculopontine tegmental nucleus (PPTg) affects control of neuronal activities between the PPN and basal ganglia in 6-OHDA lesioned rats. In order to identify the effect of low frequency stimulation on the PPTg, neuronal activity in both the STN and substantia nigra par reticulata (SNr) were recorded and subjected to quantitative analysis, including analysis of firing rates and firing patterns. In this study, we found that the firing rates of the STN and SNr were suppressed during low frequency stimulation of the PPTg. However, the firing pattern, in contrast to the firing rate, did not exhibit significant changes in either the STN or SNr of 6-OHDA lesioned rats during low frequency stimulation of the PPTg. In addition, we also found that the firing rate of STN and SNr neurons displaying burst and random pattern were decreased by low frequency stimulation of PPTg, while the neurons displaying regular pattern were not affected. These results indicate that low frequency stimulation of the PPTg affects neuronal activity in both the STN and SNr, and may represent electrophysiological efficacy of low frequency PPN stimulation.

Invasive and non-invasive neuromodulation in movement disorders.

Event Abstract Back to Event Invasive and non-invasive neuromodulation in movement disorders. Alain Maertens De Noordhout1* 1 University of Liege, University department of Neurology, Belgium In the last 25 years, invasive electrical stimulation (DBS) of several regions of the brain has been developed to alleviate symptoms of various movement disorders. Thalamic stimulation in severe essential tremor was first shown to provide long-term relief in many patients. A few years later, similar procedures have been successful in controlling major motor signs of Parkinson's disease with electrodes located in STN or GPi, and in severe dystonia with the latter target. Even dopa-resistant freezing of gait was reportedly reduced with high frequency stimulation of pedunculopontine nucleus. However, none of these interventions has so far proven any influence on the natural course of underlying illnesses. Yet, controlled studies have confirmed that DBS significantly improves QoL of patients, at least for some years. In neurodegenerative processes an particularly PD, it seems that QoL declines over years due to the lack of control of newly appearing symptoms such as dementia and postural disturbances. Non-invasive devices including rTMS and TDCS have also been used in such disorders but their effects remain debated and, even if sometimes positive, stay transient, thus needing repeated treaatment sessions. Lack of standardization of methods may account for some discrepancy of results. In coming years, it might be that restorative techniques using viral vectors could for the first time influence the natural course of illnesses such as Parkinson's disease. Keywords: DBS, rTMS, TCDS, Movement Disorders, Neuromodulation, neurorepair Conference: Belgian Brain Council 2014 MODULATING THE BRAIN: FACTS, FICTION, FUTURE, Ghent, Belgium, 4 Oct - 4 Oct, 2014. Presentation Type: Oral Presentation Topic: Clinical Neuroscience Citation: Maertens De Noordhout A (2014). Invasive and non-invasive neuromodulation in movement disorders.. Conference Abstract: Belgian Brain Council 2014 MODULATING THE BRAIN: FACTS, FICTION, FUTURE. doi: 10.3389/conf.fnhum.2014.214.00019 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 29 Jun 2014; Published Online: 30 Jun 2014. * Correspondence: Prof. Alain Maertens De Noordhout, University of Liege, University department of Neurology, Liege, B-4000, Belgium, al.maertens@chu.ulg.ac.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Alain Maertens De Noordhout Google Alain Maertens De Noordhout Google Scholar Alain Maertens De Noordhout PubMed Alain Maertens De Noordhout Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Mitochondrial Abnormality Associates with Type-Specific Neuronal Loss and Cell Morphology Changes in the Pedunculopontine Nucleus in Parkinson Disease

Cholinergic neuronal loss in the pedunculopontine nucleus (PPN) associates with abnormal functions, including certain motor and nonmotor symptoms. This realization has led to low-frequency stimulation of the PPN for treating patients with Parkinson disease (PD) who are refractory to other treatment modalities. However, the molecular mechanisms underlying PPN neuronal loss and the therapeutic substrate for the clinical benefits following PPN stimulation remain poorly characterized, hampering progress toward designing more efficient therapies aimed at restoring the PPN's normal functions during progressive parkinsonism. Here, we investigated postmortem pathological changes in the PPN of PD cases. Our study detected a loss of neurons producing gamma-aminobutyric acid (GABA) as their output and glycinergic neurons, along with the pronounced loss of cholinergic neurons. These losses were accompanied by altered somatic cell size that affected the remaining neurons of all neuronal subtypes studied here. Because studies showed that mitochondrial dysfunction exists in sporadic PD and in PD animal models, we investigated whether altered mitochondrial composition exists in the PPN. A significant up-regulation of several mitochondrial proteins was seen in GABAergic and glycinergic neurons; however, cholinergic neurons indicated down-regulation of the same proteins. Our findings suggest an imbalance in the activity of key neuronal subgroups of the PPN in PD, potentially because of abnormal inhibitory activity and altered cholinergic outflow.

Pedunculopontine nucleus stimulation: A novel therapeutic technique in intractable epilepsy

Intractable epilepsy accounts for approximately 30% cases of epilepsy worldwide, and continues to pose a medical challenge even today. Several studies have demonstrated the strong anti-epileptic influence of rapid eye movement (REM) sleep in humans, some researchers even claiming it as the most potent anti-epileptic state in human sleep–wake cycle. A reduction of REM sleep is a common feature reported in various forms of intractable epilepsy. Several studies have reported reduction to total disappearance of even the severe EEG abnormalities in West syndrome during REM sleep suggesting an explorable relation between the reduction of REM sleep and severity/intractability of seizures.

Improvement of pisa syndrome with contralateral pedunculopontine stimulation

Pedunculopontine nucleus (PPN) deep brain stimulation (DBS) has been proposed to improve gait freezing and other axial motor features in advanced Parkinson’s disease (PD) patients [1–4]. However, its effects on abnormal posture such as Pisa syndrome [5] have not been specifically described. A 62-year-old right handed woman presented with a six-year history of PD, initially manifesting as right hand resting tremor and difficulty writing. Tremor, rigidity and bradykinesia responded well to dopaminergic medications. After 5-year disease duration, she developed right sided axial lean and postural instability with falls occurring 2–3 times daily. Plain films demonstrated complex sigmoid scoliosis with mild dextroscoliosis within the thoracic spine, without osteoporosis. Trials of rotigotine, donepezil, and amantadine did not reduce fall frequency. Therefore, she was referred for PPN DBS surgery. Medications at the time of pre-surgical evaluation included carbidopa/levodopa 25/100 1.5 tabs five times daily and pramipexole 3 mg daily. Pre-operative off-medication motor UPDRS score was 18.5/108, with right upper extremity resting tremor, right greater than left rigidity, mild focal bradykinesia in the hands, slow gait with significant right tilt, and mild but recoverable retropulsion on pull test. The motor score improved to 12.5/108, 30 minutes after 350 mg levodopa challenge. She was offered left lead implantation given right greater than left PD severity. Left PPN DBS surgery was performed at the Toronto Western Hospital under local anesthesia. The surgical procedure has been previously described [2]. An implantable pulse generator (Soletra, Medtronic, Inc.) was implanted the same day under general anesthesia. She tolerated surgery well, aside from mild post-operative encephalopathy and word finding difficulty which recovered within two weeks. Programming of the left PPN stimulation started 1 month after surgery. The patient was programmed weekly using monopolar stimulation at each contact at 1.0V, at 20Hz, 50Hz, 70Hz and 130Hz over 16 weeks. The patient kept a diary of falls, which significantly decreased from 2–3 falls/daily to less than 1 fall per week. The best setting was found as contacts 3+ 2−/1.5V/90μsec/130Hz. Videos taken throughout 14 months of follow-up demonstrate progressive improvement of her asymmetric bradykinetic gait and right axial lean (Video). Lateral flexion of the trunk has been described in PD, either as scoliosis related to parkinsonism with leaning usually opposite the most affected side or as Pisa syndrome, originally described as an axial dystonia in patients treated with neuroleptics but also seen in patients with PD [5]. Prior studies of PPN DBS in PD patients have not described significant alterations in axial lean, which can contribute significantly to falls and postural instability whereas several small case series and reports describe mixed results of STN DBS on various postural abnormalities including Pisa syndrome [6]. Stimulation of the PPN and surrounding pontomesencephalic tegmental field may not only affect gait but also extensor muscle tone, thus leading to changes in posture. Chronic electrical stimulation of ventral parts of this region in freely moving cats is accompanied by an increase in tone and facilitation of walking [7]. Based on this patient’s improvement in Pisa syndrome following PPN DBS, we suggest that further studies investigating the impact of PPN DBS closely examine postural abnormalities prior to and following stimulation. The video demonstrates pre- and post-operative gait and posture examinations all taken 3 hours post-levodopa intake. The improvement in the axial lean was temporally related to the reduction of falls.

Clinical outcomes from bilateral versus unilateral stimulation of the pedunculopontine nucleus with and without concomitant caudal zona incerta region stimulation in Parkinson's disease

Introduction. The Pedunculopontine nucleus is a novel target for deep brain stimulation and this may improve postural instability and gait dysfunction in Parkinson's disease. If unilateral Pedunculopontine nucleus stimulation is as efficacious as bilateral stimulation this would lead to less surgical risk. Methods. 5 Parkinson's disease patients with bilateral caudal Zona Incerta region and Pedunculopontine nucleus electrodes were assessed using the motor component of the Unified Parkinson's Disease Rating Scale. Patients were assessed in the on-medication state to determine the optimal combination of stimulation setting for axial symptom control. Results. The on-medication composite axial-subscore only showed a statistically significant improvement when bilateral Pedunculopontine nucleus and caudal Zona Incerta region stimulation was used. Conclusions. In the on-medication state bilateral Pedunculopontine nucleus and caudal Zona Incerta region stimulation is required in order to produce a significant change in the motor Unified Parkinson's Disease Rating Scale axial-subscore from baseline.