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

Interference of functional dual-tasks on gait in untrained people with Parkinson's disease and healthy controls: a cross-sectional study

[EN] Background In Parkinson's disease (PD) population, performing secondary tasks while walking further deteriorates gait and restrict mobility in functional contexts of daily life. This study (1) analyzed the interference of functional cognitive and motor secondary task on untrained people with PD and (2) compared their walking with healthy subjects. Methods Forty people with PD (aged 66.72 [7.5] years, Hoehn and Yahr stage I-II-III, on-medication) composed the PD group (PDG) and 43 participants (aged 66.60 [8.75] years) formed the group of healthy counterparts (HG). Gait was evaluated through spatiotemporal, kinematic and kinetic outcomes in five conditions: single task (ST) and visual, verbal, auditory and motor dual-task (DT). Results The velocity, stride length, and braking force performance of both groups was statistically higher in the ST condition than in verbal, auditory and motor DT (p.05). Conclusions: In untrained participants with PD, verbal and motor secondary tasks affect gait significantly, while auditory and visual tasks interfere to a lesser extent. Untrained people with PD have a poorer gait performance than their healthy counterparts, but in different grades according to the analyzed variables. Trial registration The data in this paper are part of a single-blind, randomized, controlled trial and correspond to the evaluations performed before a physical rehabilitation program, retrospectively registered with the number at clinicaltrial.govNCT04038866.San Martín Valenzuela, C.; Dueñas Moscardó, L.; Lopez Pascual, J.; Serra-Añó, P.; Tomás, JM. (2020). Interference of functional dual-tasks on gait in untrained people with Parkinson's disease and healthy controls: a cross-sectional study. BMC Musculoskeletal Disorders. 21(1):1-11. https://doi.org/10.1186/s12891-020-03431-xS111211Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008;79:368–76.Soh S-E, McGinley JL, Watts JJ, Iansek R, Murphy AT, Menz HB, et al. Determinants of health-related quality of life in people with Parkinson’s disease: a path analysis. Qual Life Res. 2013;22:1543–53.Tan D, Danoudis M, McGinley J, Morris ME. Relationships between motor aspects of gait impairments and activity limitations in people with Parkinson’s disease: a systematic review. Parkinsonism Relat Disord. 2012;18:117–24.Kelly VE, Eusterbrock AJ, Shumway-Cook A. A review of dual-task walking deficits in people with Parkinson’s disease: motor and cognitive contributions, mechanisms, and clinical implications. Parkinson’s Disease. 2012;918719.Sofuwa O, Nieuwboer A, Desloovere K, Willems A-M, Chavret F, Jonkers I. Quantitative gait analysis in Parkinson’s disease: comparison with a healthy control group. Arch Phys Med Rehabil. 2005;86:1007–13.Beauchet O, Berrut G. Gait and dual-task: definition, interest, and perspectives in the elderly. Psychologie et NeuroPsychiatrie du Vieillissement. 2006;4:215–25.Raffegeau TE, Krehbiel LM, Kang N, Thijs FJ, Altmann LJP, Cauraugh JH, et al. A meta-analysis: Parkinson’s disease and dual-task walking. Parkinsonism Relat Disord. 2019 May;62:28–35.Eric R. Kandel, James H. Schwartz, Thomas M. Jessell, Steven a. Siegelbaum, A. J. Hudspeth. Principles of neural science. Fifth edition. McGraw-Hill Medical: United States of America; 2013.Eisinger RS, Cernera S, Gittis A, Gunduz A, Okun MS. A review of basal ganglia circuits and physiology: application to deep brain stimulation. Parkinsonism Relat Disord. 2019 Feb;59:9–20.Isella V, Mapelli C, Morielli N, De Gaspari D, Siri C, Pezzoli G, et al. Validity and metric of MiniMental Parkinson and MiniMental state examination in Parkinson’s disease. Neurol Sci. 2013;34:1751–8.Morris ME, McGinley J, Huxham F, Collier J, Iansek R. Constraints on the kinetic, kinematic and spatiotemporal parameters of gait in Parkinson’s disease. Hum Mov Sci. 1999;18:461–83.Brauer SG, Morris ME. Can people with Parkinson’s disease improve dual tasking when walking? Gait & Posture. 2010;31:229–33.Baron EI, Miller Koop M, Streicher MC, Rosenfeldt AB, Alberts JL. Altered kinematics of arm swing in Parkinson’s disease patients indicates declines in gait under dual-task conditions. Parkinsonism Relat Disord. 2018;48:61–7.Rochester L, Galna B, Lord S, Burn D. The nature of dual-task interference during gait in incident Parkinson’s disease. Neuroscience. 2014;265:83–94.Logan D, Kiemel T, Dominici N, Cappellini G, Ivanenko Y, Lacquaniti F, et al. The many roles of vision during walking. Exp Brain Res. 2010;206:337–50.de Luna RA, Mihailovic A, Nguyen AM, Friedman DS, Gitlin LN, Ramulu PY. The Association of Glaucomatous Visual Field Loss and Balance. Transl Vis Sci Technol. 2017 May 22;6(3):8.Suarez H, Geisinger D, Ferreira ED, Nogueira S, Arocena S, Roman CS, et al. Balance in Parkinson’s disease patients changing the visual input. Brazilian Journal of Otorhinolaryngology. 2011;77:651–5.Wu T, Hallett M. Neural correlates of dual task performance in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2008;79:760–6.Canning CG. The effect of directing attention during walking under dual-task conditions in Parkinson’s disease. Parkinsonism Relat Disord. 2005;11:95–9.Wu T, Liu J, Zhang H, Hallett M, Zheng Z, Chan P. Attention to automatic movements in Parkinson’s disease: modified automatic mode in the striatum. Cereb Cortex. 2015;25:3330–42.de Roiz R. M, Cacho EWA, Pazinatto MM, Reis JG, Cliquet a. Barasnevicius-Quagliato EMA Gait analysis comparing Parkinson’s disease with healthy elderly subjects Arq Neuropsiquiatr. 2010;68:81–6.Grabli D, Karachi C, Welter M-L, Lau B, Hirsch EC, Vidailhet M, et al. Normal and pathological gait: what we learn from Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2012 Oct;83(10):979–85.Anna C, Serena F, Maurizio F. Del Sorbo Francesca, Romito Luigi M., Elia Antonio E., et al. quantitative gait analysis in parkin disease: possible role of dystonia. Mov Disord. 2016;31:1720–8.Morris M, Iansek R, McGinley J, Matyas T, Huxham F. Three-dimensional gait biomechanics in Parkinson’s disease: evidence for a centrally mediated amplitude regulation disorder. Mov Disord. 2005;20:40–50.Peterson CL, Kautz SA, Neptune RR. Braking and propulsive impulses increase with speed during accelerated and decelerated walking. Gait Posture. 2011;33:562–7.Chiu M-C, Wang M-J. The effect of gait speed and gender on perceived exertion, muscle activity, joint motion of lower extremity, ground reaction force and heart rate during normal walking. Gait & Posture. 2007;25:385–92.Muniz AMS, Liu H, Lyons KE, Pahwa R, Liu W, Nobre FF, et al. Comparison among probabilistic neural network, support vector machine and logistic regression for evaluating the effect of subthalamic stimulation in Parkinson disease on ground reaction force during gait. J Biomech. 2010;43:720–6.Chastan N, Do MC, Bonneville F, Torny F, Bloch F, Westby GWM, et al. Gait and balance disorders in Parkinson’s disease: impaired active braking of the fall of Centre of gravity. Mov Disord. 2009;24:188–95.Perneger T. What's wrong with Bonferroni adjustments. BMJ. 1998 Apr 18;316(7139):1236–8

Multiple rib fractures due to dystonia in a multiple system atrophy-Parkinsonian patient

International audienc

Usefulness of multidetector-row computerized tomographic angiography for the surgical planning in stereoelectroencephalography

International audienc

Effects of nigral stimulation on locomotion and postural stability in patients with Parkinson's disease.

International audienceThe physiopathology of gait and balance disorders in Parkinson's disease patients is still poorly understood. Levodopa treatment and subthalamic nucleus (STN) stimulation improve step length and walking speed, with less effect on postural instability. These disorders have been linked to dysfunction of the descending basal ganglia outputs to brainstem structures. In this study, we evaluated the effects of stimulation of the substantia nigra pars reticulata (SNr), on locomotion and balance in Parkinson's disease patients. Biomechanical parameters and leg muscle activity were recorded during gait initiation in seven selected patients operated for bilateral STN stimulation, out of 204 stimulated patients, with one contact of each electrode located within the SNr. Step length, anteroposterior and vertical velocities of the centre of gravity were studied, with special reference to the subjects' ability to brake the centre of gravity fall before foot-contact, and compared to seven controls. In Parkinson's disease patients, five treatment conditions were tested: (i) no treatment, (ii) levodopa treatment, (iii) STN stimulation, (iv) SNr stimulation and (v) combined levodopa treatment and STN stimulation. The effects of these treatments on motor parkinsonian disability were assessed with the UPDRS III scale, separated into 'axial' (rising from chair, posture, postural stability and gait) and 'distal' scores. Whereas levodopa and/or STN stimulation improved 'axial' and 'distal' motor symptoms, SNr stimulation improved only the 'axial' symptoms. Compared to controls, untreated Parkinson's disease patients showed reduced step length and velocity, and poor braking just prior to foot-contact, with a decrease in both soleus (S) and anterior tibialis (AT) muscle activity. Step length and velocity significantly increased with levodopa treatment alone or in combination with STN stimulation in both natural and fast gait conditions, and with STN stimulation alone in the fast gait condition. Conversely, SNr stimulation had no significant effect on these measures in either condition. In the natural gait condition, no fall in the centre of gravity occurred as step length was low and active braking was unnecessary. In the fast gait condition, braking was improved with STN or SNr stimulation but not with levodopa treatment, with an increase in the stance leg S muscle activity. These results suggest that anteroposterior (length and velocity) and vertical (braking capacity) gait parameters are controlled by two distinct systems within the basal ganglia circuitry, representing respectively locomotion and balance. The SNr, a major basal ganglia output known to project to pontomesencephalic structures, is postulated as being particularly involved in balance control during gait