Pedunculopontine nucleus area oscillations during stance, stepping and freezing in Parkinson's disease.

International audienceThe pedunculopontine area (PPNa) including the pedunculopontine and cuneiform nuclei, belongs to the mesencephalic locomotor region. Little is known about the oscillatory mechanisms underlying the function of this region in postural and gait control. We examined the modulations of the oscillatory activity of the PPNa and cortex during stepping, a surrogate of gait, and stance in seven Parkinson's disease patients who received bilateral PPNa implantation for disabling freezing of gait (FOG). In the days following the surgery, we recorded behavioural data together with the local field potentials of the PPNa during sitting, standing and stepping-in-place, under two dopaminergic medication conditions (OFF and ON levodopa). Our results showed that OFF levodopa, all subjects had FOG during step-in-place trials, while ON levodopa, stepping was effective (mean duration of FOG decreasing from 61.7±36.1% to 7.3±10.1% of trial duration). ON levodopa, there was an increase in PPNa alpha (5-12 Hz) oscillatory activity and a decrease in beta (13-35 Hz) and gamma (65-90 Hz) bands activity. PPNa activity was not modulated during quiet standing and sitting. Our results confirm the role of the PPNa in the regulation of gait and suggest that, in Parkinson disease, gait difficulties could be related to an imbalance between low and higher frequencies

A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation

Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson’s disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients’ usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral

Combined STN/SNr-DBS for the treatment of refractory gait disturbances in Parkinson's disease: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Severe gait disturbances in idiopathic Parkinson's disease (PD) are observed in up to 80% of all patients in advanced disease stages with important impact on quality of life. There is an unmet need for further symptomatic therapeutic strategies, particularly as gait disturbances generally respond unfavourably to dopaminergic medication and conventional deep brain stimulation of the subthalamic nucleus in advanced disease stages. Recent pathophysiological research pointed to nigro-pontine networks entrained to locomotor integration. Stimulation of the pedunculopontine nucleus is currently under investigation, however, hitherto remains controversial. The substantia nigra pars reticulata (SNr) - entrained into integrative locomotor networks - is pathologically overactive in PD. High-frequent stimulation of the substantia nigra pars reticulata preferentially modulated axial symptoms and therefore is suggested as a novel therapeutic candidate target for neuromodulation of refractory gait disturbances in PD.</p> <p>Methods</p> <p>12 patients with idiopathic Parkinson's disease and refractory gait disturbances under best individual subthalamic nucleus stimulation and dopaminergic medication will be enroled into this double-blind 2 × 2 cross-over clinical trial. The treatment consists of two different stimulation settings using <it>(i) </it>conventional stimulation of the subthalamic nucleus [STNmono] and <it>(ii) </it>combined stimulation of distant electrode contacts located in the subthalamic nucleus and caudal border zone of STN and substantia nigra pars reticulata [STN+SNr]. The primary outcome measure is the change of the cumulative 'axial score' (UPDRS II items '13-15' and UPRDS III items '27-31') at three weeks of constant stimulation in either condition. Secondary outcome measures include specific scores on freezing of gait, balance function, quality of life, non-motor symptoms, and neuropsychiatric symptoms. The aim of the present trial is to investigate the efficacy and safety of a three week constant combined stimulation on [STN+SNr] compared to [STNmono]. The results will clarify, whether stimulation on nigral contacts additional to subthalamic stimulation will improve therapeutic response of otherwise refractory gait disturbances in PD.</p> <p>Trial registration</p> <p>The trial was registered with the clinical trials register of <url>http://www.clinicaltrials.gov</url> (<a href="http://www.clinicaltrials.gov/ct2/show/NCT01355835">NCT01355835</a>)</p

The pedunculopontine tegmental nucleus - A functional hypothesis from the comparative literature

We present data from animal studies showing that the pedunculopontine tegmental nucleus-conserved through evolution, compartmentalized, and with a complex pattern of inputs and outputs-has functions that involve formation and updates of action-outcome associations, attention, and rapid decision making. This is in contrast to previous hypotheses about pedunculopontine function, which has served as a basis for clinical interest in the pedunculopontine in movement disorders. Current animal literature points to it being neither a specifically motor structure nor a master switch for sleep regulation. The pedunculopontine is connected to basal ganglia circuitry but also has primary sensory input across modalities and descending connections to pontomedullary, cerebellar, and spinal motor and autonomic control systems. Functional and anatomical studies in animals suggest strongly that, in addition to the pedunculopontine being an input and output station for the basal ganglia and key regulator of thalamic (and consequently cortical) activity, an additional major function is participation in the generation of actions on the basis of a first-pass analysis of incoming sensory data. Such a function-rapid decision making-has very high adaptive value for any vertebrate. We argue that in developing clinical strategies for treating basal ganglia disorders, it is necessary to take an account of the normal functions of the pedunculopontine. We believe that it is possible to use our hypothesis to explain why pedunculopontine deep brain stimulation used clinically has had variable outcomes in the treatment of parkinsonism motor symptoms and effects on cognitive processing. © 2016 International Parkinson and Movement Disorder Society

The pedunculopontine tegmental nucleus - A functional hypothesis from the comparative literature

We present data from animal studies showing that the pedunculopontine tegmental nucleus-conserved through evolution, compartmentalized, and with a complex pattern of inputs and outputs-has functions that involve formation and updates of action-outcome associations, attention, and rapid decision making. This is in contrast to previous hypotheses about pedunculopontine function, which has served as a basis for clinical interest in the pedunculopontine in movement disorders. Current animal literature points to it being neither a specifically motor structure nor a master switch for sleep regulation. The pedunculopontine is connected to basal ganglia circuitry but also has primary sensory input across modalities and descending connections to pontomedullary, cerebellar, and spinal motor and autonomic control systems. Functional and anatomical studies in animals suggest strongly that, in addition to the pedunculopontine being an input and output station for the basal ganglia and key regulator of thalamic (and consequently cortical) activity, an additional major function is participation in the generation of actions on the basis of a first-pass analysis of incoming sensory data. Such a function-rapid decision making-has very high adaptive value for any vertebrate. We argue that in developing clinical strategies for treating basal ganglia disorders, it is necessary to take an account of the normal functions of the pedunculopontine. We believe that it is possible to use our hypothesis to explain why pedunculopontine deep brain stimulation used clinically has had variable outcomes in the treatment of parkinsonism motor symptoms and effects on cognitive processing. © 2016 International Parkinson and Movement Disorder Society

Freezing of gait and fall detection in Parkinson’s disease using wearable sensors:a systematic review

Despite the large number of studies that have investigated the use of wearable sensors to detect gait disturbances such as Freezing of gait (FOG) and falls, there is little consensus regarding appropriate methodologies for how to optimally apply such devices. Here, an overview of the use of wearable systems to assess FOG and falls in Parkinson’s disease (PD) and validation performance is presented. A systematic search in the PubMed and Web of Science databases was performed using a group of concept key words. The final search was performed in January 2017, and articles were selected based upon a set of eligibility criteria. In total, 27 articles were selected. Of those, 23 related to FOG and 4 to falls. FOG studies were performed in either laboratory or home settings, with sample sizes ranging from 1 PD up to 48 PD presenting Hoehn and Yahr stage from 2 to 4. The shin was the most common sensor location and accelerometer was the most frequently used sensor type. Validity measures ranged from 73–100% for sensitivity and 67–100% for specificity. Falls and fall risk studies were all home-based, including samples sizes of 1 PD up to 107 PD, mostly using one sensor containing accelerometers, worn at various body locations. Despite the promising validation initiatives reported in these studies, they were all performed in relatively small sample sizes, and there was a significant variability in outcomes measured and results reported. Given these limitations, the validation of sensor-derived assessments of PD features would benefit from more focused research efforts, increased collaboration among researchers, aligning data collection protocols, and sharing data sets

Temporal-spatial profiling of pedunculopontine galanin-cholinergic neurons in the lactacystin rat model of Parkinson’s disease

Parkinson’s disease (PD) is conventionally seen as resulting from single-system neurodegeneration affecting nigrostriatal dopaminergic neurons. However, accumulating evidence indicates a multi-system degeneration and neurotransmitter deficiencies, including cholinergic neurons which degenerate in a brainstem nucleus, the pedunculopontine nucleus (PPN), resulting in motor- and cognitive impairments. The neuropeptide galanin can inhibit cholinergic transmission, whilst being upregulated in degenerating brain regions associated with cognitive decline. Here we determined the temporal-spatial profile of progressive expression of endogenous galanin within degenerating cholinergic neurons, across the rostro-caudal axis of the PPN, by utilising the lactacystin-induced rat model of PD. First, we show progressive neuronal death affecting nigral dopaminergic and PPN cholinergic neurons, reflecting that seen in PD patients, to facilitate use of this model for assessing the therapeutic potential of bioactive peptides. Next, stereological analyses of the lesioned brain hemisphere found that the number of PPN cholinergic neurons expressing galanin increased by 11%, compared to sham-lesioned controls, increasing by a further 5% as the neurodegenerative process evolved. Galanin upregulation within cholinergic PPN neurons was most prevalent closest to the intra-nigral lesion site, suggesting that galanin upregulation in such neurons adapt intrinsically to neurodegeneration, to possibly neuroprotect. This is the first report on the extent and pattern of galanin expression in cholinergic neurons across distinct PPN subregions in both the intact rat CNS and lactacystin lesioned rats. The findings pave the way for future work to target galanin signaling in the PPN, to determine the extent to which upregulated galanin expression could offer a viable treatment strategy for ameliorating PD symptoms associated with cholinergic degeneration

EFFET DE LA STIMULATION DU NOYAU PEDONCULOPONTIN SUR LES TROUBLES DE LA MARCHE ET LE FREEZING DANS LA MALADIE DE PARKINSON : ETUDE CLINIQUE ET THERAPEUTIQUE

Gait disorders in the healthy elderly are a major public health concern. We believed understanding Parkinson Disease (PD) typical gait disorders would bring some insights into the mechanisms of gait disorders in the elderly. In PD, their response to levodopa and to subthalamic nucleus stimulation is often heterogeneous, suggesting they are controlled at different levels of the CNS. In particular, there is convergent evidence of early alterations in cholinergic neurotransmission responsible for levodopa-resistant gait disorders in PD. An example comes from the observed link between executive dysfunction and the presence of levodopa-resistant freezing. Moreover, the relative preservation of executive functions in some patients suggests that other mechanisms may be involved in the development of levodopa-resistant freezing. The pedunculopontine nucleus area (PPNa) is a likely candidate. We report a beneficial effect of PPNa stimulation on freezing and falls related to freezing in some patients. However, our results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk–benefit ratio.Les troubles de la marche constituent chez la personne âgée un problème de santé publique. Dans l'hypothèse d'un continuum vieillissement normal/maladie de Parkinson, cette dernière pourrait se révéler un bon modèle d'étude des mécanismes physiopathologiques sous-jacents aux troubles de la marche. Leur réponse à la lévodopa et à la stimulation du noyau subthalamique, souvent hétérogène, reflète l'existence d'un système de contrôle multiniveaux. En particulier, le système cholinergique dévoile de plus en plus son importance dansla survenue des troubles de la marche lévodopa-résistants. En témoigne, l'existence d'un lien entre syndrome dysexécutif et freezing de la marche lévodopa-résistant. De plus, la préservation des fonctions exécutives chez certains patients en appelle à l'existence d'autres mécanismes pouvant impliquer notamment la région du noyau pédonculopontin. Nous rapportons un effet net de sa stimulation sur le freezing et les chutes reliées au freezing chez certains patients. Les résultats apparaissent toutefois décevants au vu de l'enthousiasme des premières études et nécessitent de déterminer si l'optimisation de la sélection des patients, le ciblage et le réglage des paramètres de stimulation pourraient améliorer les résultats au point de transformer ces études de recherche clinique en un traitement présentant un rapport bénéfice-risque favorable

Développement d'un algorithme de diffraction inverse par déformations eulériennes de courbes de niveaux pour la reconstruction d'images microondes (application à l'imagerie radar)

Une méthode de diffraction inverse 2D en électromagnétisme (polarisation TM et dépendance temporelle harmonique) basée sur la reconstruction de contours, est présentée. La méthode consiste à faire évoluer des contours sous l action d une vitesse de déformation normale, jusqu à convergence vers les contours des objets inconnus. La vitesse de déformation est choisie de sorte à faire décroître une fonction coût basée sur des données en champ lointain. Les contours actifs sont considérés comme étant le niveau zéro d une fonction de distance signée, et propagée en utilisant une EDP de Halmiton-Jacobi exprimant la conservation des ensembles de niveaux sous l action d un certain champ de vitesse. Les méthodes d ensembles de niveaux présentent des caractéristiques très intéressantes pour un problème inverse telles que la possibilité de régulariser facilement les contours par l ajout d un terme de courbure au champ de vitesse et la capacité de gérer automatiquement les changements de topologie. La méthode fait appel à un algorithme de diffraction directe basé sur des équations intégrales de contours et sur une description cinématique des contours. Au lieu d utiliser les courants physiques, qui peuvent être singuliers aux pointes, des pseudo-courants sont introduits. La vitesse de déformation, exprimée en fonction des pseudo(courants physiques, s avère être d une grande précision. La technique des sauts de fréquence joue un rôle très important, les fréquences permettant de localiser les objets et d en obtenir une reconstruction approximative, et les fréquences plus élevées permettant ensuite de reconstruire les détails plus fins des objets. Des reconstructions très précises de plusieurs objets en présence sont présentées, illustrant ainsi la capacité de la méthode à gérer les changements de topologie. Des reconstructions basées sur des données bruitées, et résultant de configurations avec couverture limitée des ondes incidentes, sont ainsi présentées.We present a boundary-oriented method for 2D electromagnetic inverse scattering, in TM polarization and time-harmonic dependence. The method consists in moving some contours under a normal deformation velocity until they fit the contours of the unknown objects. The deformation velocity is appropriately chosen in such a way that a cost function, based on far-field data, is decreased after each elementary deformation. The contours of the mooring objects are viewed as the zero level set of a Hamilton-Jacobi PDE expressing the conservation of the level sets under a given velocity field. Level set methods add quite valuable features to the inverse procedure such as easy regularization of the contours with the introduction of a curvature term in the velocity field and automatic breaking and merging capability. The method uses a direct scattering algorithm based on boundary integral equations and on a kinematical description of the contours. Instead of working with the physical currents, that may be singular at corner points, pseudo-currents are introduced. The deformation velocity, written with respect to the well-behaved pseudo-currents, turns out to be highly accurate, therefore giving highly accurate constructions. The frequency hopping technique plays a very important role, as low frequencies make it possible to localize the objects and to reconstruct them roughly, and then higher frequencies allow finer details to retrieve. Very accurate reconstructions are given of several objects in presence, starting from one single initial object illustrating in the process the breaking capability of level set methods. Reconstruction results using noise-corrupted data, as well as stemming from configurations with limited coverage of the incident fields are also given.NICE-BU Sciences (060882101) / SudocSudocFranceF

Stimulation cérébrale profonde et troubles de la marche dans la maladie de Parkinson

Gait disorders and freezing of gait (FOG) are seen in most patients with advanced Parkinson disease. Response to levodopa and deep brain stimulation is variable across patients