Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Authors: Renner, Tobias J. Gawrilow, Caterina Conzelmann, Annette Giese, Martin A.; Kasneci, Enkelejda Swoboda, Walter Löchner, Johanna Bethge, Wolfgang A. Lautenbacher, Heinrich Thierfelder, Annika; Ilg, Winfried; Primbs, Jonas Seizer, Lennart Alt, Annika Kristin Kühnhausen, Jan Hollmann, Karsten Klein, Carolin S.

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Authors: Pellerin, David Seemann, Jens; Traschütz, Andreas Brais, Bernard Ilg, Winfried; Synofzik, Matthis

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Abstract:

Background and Objectives With targeted treatment trials on the horizon, identification of sensitive and valid outcome measures becomes a priority for the >100 spastic ataxias. Digital-motor measures, assessed by wearable sensors, are prime outcome candidates for SPG7 and other spastic ataxias. We here aimed to identify candidate digital-motor outcomes for SPG7 – as one of the most common spastic ataxias – that: (i) reflect patient-relevant health aspects, even in mild, trial-relevant disease stages; (ii) are suitable for a multi-center setting; and (iii) assess mobility also during uninstructed walking simulating real-life.

Authors: Beichert, Lukas Seemann, Jens; Kessler, Christoph Traschütz, Andreas Müller, Doreen Dillmann-Jehn, Katrin Ricca, Ivana Satolli, Sara Başak, Ayşe Nazli Coarelli, Giulia Timmann, Dagmar Gagnon, Cynthia van de Warrenburg, Bart P. Ilg, Winfried; Synofzik, Matthis Schüle, Rebecca

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Abstract:

BACKGROUND With disease-modifying drugs in reach for cerebellar ataxias, fine-grained digital health measures are highly warranted to complement clinical and patient-reported outcome measures in upcoming treatment trials and treatment monitoring. These measures need to demonstrate sensitivity to capture change, in particular in the early stages of the disease.OBJECTIVE To unravel gait measures sensitive to longitudinal change in the - particularly trial-relevant- early stage of spinocerebellar ataxia type 2 (SCA2).METHODS Multi-center longitudinal study with combined cross-sectional and 1-year interval longitudinal analysis in early-stage SCA2 participants (n=23, including 9 pre-ataxic expansion carriers; median ATXN2 CAG repeat expansion 38{\textpm}2; median SARA [Scale for the Assessment and Rating of Ataxia] score 4.83{\textpm}4.31). Gait was assessed using three wearable motion sensors during a 2-minute walk, with analyses focusing on gait measures of spatiotemporal variability shown sensitive to ataxia severity, e.g. lateral step deviation.RESULTS We found significant changes for gait measures between baseline and 1-year follow-up with large effect sizes (lateral step deviation p=0.0001, effect size rprb=0.78), whereas the SARA score showed no change (p=0.67). Sample size estimation indicates a required cohort size of n=43 to detect a 50\% reduction in natural progression. Test-retest reliability and Minimal Detectable Change analysis confirm the accuracy of detecting 50\% of the identified 1-year change.CONCLUSIONS Gait measures assessed by wearable sensors can capture natural progression in early-stage SCA2 within just one year {\textendash} in contrast to a clinical ataxia outcome. Lateral step deviation thus represents a promising outcome measure for upcoming multi-centre interventional trials, particularly in the early stages of cerebellar ataxia.Competing Interest StatementJ. Seemann, L. Daghsen, M. Cazier, J. Lamy, ML. Welter, A. Giese, and G. Coarelli report no disclosures. Prof. Durr serves as an advisor to Critical Path Ataxia Therapeutics Consortium and her institution (Paris Brain institute) receives her consulting fees from Pfizer, Huntix, UCB, Reata, PTC Therapeutics as well as research grants from the NIH, Biogen, Servier, and the National Clinical Research Program and she holds partly a Patent B 06291873.5 on Anaplerotic Therapy of Huntington{\textquoteright}s Disease and other polyglutamine diseases (2006). Prof. Synofzik has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra, and Lilly, all unrelated to the present manuscript. Dr. Ilg received consultancy honoraria by Ionis Pharmaceuticals, unrelated to the present work. Funding StatementWe would like to thank all the participants including in this study. We would like to thank BIOGEN and IONIS which funded the NCT04288128 study and INSERM, which sponsored the NCT04288128 study (to A. D.). This work was supported by the International Max Planck Research School for Intelligent Systems (IMPRS-IS) (to J.S.) and the Else Kroener-Fresenius-Stiftung Medical Scientist programme ClinbrAIn (to W.I.), as well as the Else Kroener-Fresenius Stiftung Clinician Scientist programme PRECISE.net (to M.S.). Work on this project was supported, in part, by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) No 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP 825575 (to M.S. and A.D.).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics committee/IRB of Sorbonne universite and University Tuebingen, Germany gave ethical approval for this workI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesData will be made available upon reasonable request. The authors confirm that the data supporting the findings of this study are available within the article. Raw data regarding human subjects (e.g. clinical data) are not shared freely to protect the privacy of the human subjects involved in this study; no consent for open sharing has been obtained.

Authors: Seemann, Jens; Daghsen, Lina Cazier, Mathieu Lamy, Jean-Charles Welter, Marie-Laure Giese, Martin A.; Synofzik, Matthis Durr, Alexandra Ilg, Winfried; Coarelli, Giulia

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Authors: Ilg, Winfried; Milne, Sarah Schmitz-Hübsch, Tanja Alcock, Lisa Beichert, Lukas Bertini, Enrico Ibrahim, Norlinah Dawes, Helen Gomez, Christopher Hanagasi, Hasmet Kinnunen, Kirsi Minnerop, Martina Németh, Andrea Newman, Jane Ng, Yi Shiau Rentz, Clara Samanci, Bedia Shah, Vrutang Summa, Susanna Horak, Fay

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Abstract:

Abstract. Wearable inertial measurement units (IMU) enable largescale multicenter studies of everyday gait analysis in patients with rare neurodegenerative diseases such as cerebellar ataxia. To date, the quantity of sensors used in such studies has involved a trade-off between data quality and clinical feasibility. Here, we apply machine learning techniques to potentially reduce the number of sensors required for real-life gait analysis from three sensors to a single sensor on the hip. We trained 1D-CNNs on constrained walking data from individuals with cerebellar ataxia and healthy controls to generate synthetic foot data and predict gait features from a single sensor and tested them in free walking conditions, including the everyday life of unseen subjects. We compare 14 stride-based gait features (e.g. stride length) with three sensors (two on the feet and one on the hip) with our approach estimating the same features based on raw IMU-data from a single sensor placed on the hip. Leveraging layer-wise relevance propagation (LRP) and transfer learning, we determine driving elements of the input signals to predict individuals’ gait features. Our approach achieved a relative error (

Authors: Seemann, Jens; Loris, Tim Weber, Lukas Synofzik, Matthis Giese, Martin A.; Ilg, Winfried

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Abstract:

Since neural networks play an increasingly important role in critical sectors, explaining network predictions has become a key research topic. Counterfactual explanations can help to understand why classifier models decide for particular class assignments and, moreover, how the respective input samples would have to be modified such that the class prediction changes. Previous approaches mainly focus on image and tabular data. In this work we propose SPARCE, a generative adversarial network (GAN) architecture that generates SPARse Counterfactual Explanations for multivariate time series. Our approach provides a custom sparsity layer and regularizes the counterfactual loss function in terms of similarity, sparsity, and smoothness of trajectories. We evaluate our approach on real-world human motion datasets as well as a synthetic time series interpretability benchmark. Although we make significantly sparser modifications than other approaches, we achieve comparable or better performance on all metrics. Moreover, we demonstrate that our approach predominantly modifies salient time steps and features, leaving non-salient inputs untouched.

Authors: Lang, Jana Giese, Martin A.; Ilg, Winfried; Otte, Sebastian

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Abstract:

Background In Hereditary Spastic Paraplegia (HSP) type 4 (SPG4) a length-dependent axonal degeneration in the cortico-spinal tract leads to progressing symptoms of hyperrefexia, muscle weakness, and spasticity of lower extremities. Even before the manifestation of spastic gait, in the prodromal phase, axonal degeneration leads to subtle gait changes. These gait changes - depicted by digital gait recording - are related to disease severity in prodromal and early-to-moderate manifest SPG4 participants. Methods We hypothesize that dysfunctional neuro-muscular mechanisms such as hyperrefexia and muscle weak- ness explain these disease severity-related gait changes of prodromal and early-to-moderate manifest SPG4 partici- pants. We test our hypothesis in computer simulation with a neuro-muscular model of human walking. We introduce neuro-muscular dysfunction by gradually increasing sensory-motor refex sensitivity based on increased velocity feedback and gradually increasing muscle weakness by reducing maximum isometric force. Results By increasing hyperrefexia of plantarfexor and dorsifexor muscles, we found gradual muscular and kin- ematic changes in neuro-musculoskeletal simulations that are comparable to subtle gait changes found in prodromal SPG4 participants. Conclusions Predicting kinematic changes of prodromal and early-to-moderate manifest SPG4 participants by grad- ual alterations of sensory-motor refex sensitivity allows us to link gait as a directly accessible performance marker to emerging neuro-muscular changes for early therapeutic interventions. Keywords Gait simulation, Spasticity, Hyperrefexia, Prodromal, SPG4, HSP, Movement disorder

Authors: Laßmann, Christian; Ilg, Winfried; Rattay, Tim W. Schöls, Ludger Giese, Martin A.; Haeufle, Daniel F. B.

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Authors: Ilg, Winfried; Timmann, Dagmar

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: In Book

Chapter: Essentials

Pages: 709–714

Publisher: Springer, Cham

Month: March

ISBN: 978-3-031-15070-8

Abstract:

In this chapter, methods will be introduced which are currently available to perform lesion-symptom mapping in patients with focal and degenerative cerebellar disease. At the beginning of the chapter, strength and weaknesses inherent in studies on localization of cerebellar function in these different patient populations will be discussed. Next, methods of lesion-symptom mapping in focal cerebellar disease will be explained in more detail including lesion delineation, lesion normalization, and descriptive and inferential statistical analysis. Finally, methods of lesion-symptom mapping in cerebellar degeneration and available atlases of the cerebellum in stereotaxic space will be introduced.

Authors: Timmann, D. Ernst, T. M. Ilg, Winfried; Donchin, Opher

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: In Book

Abstract:

In this chapter, drug treatment in the few treatable causes of degenerative ataxias will first be presented including vitamin deficiency, metabolic disorders, and autoimmune disorders. Next, older and more recent drug trials will be discussed which have been performed in Friedreich’s ataxia and may lead to effective drug treatments in the future. Finally, it will be shown that, as yet, symptomatic treatments of most degenerative ataxias are lacking, that is, there is still no “anti-ataxic drug.” The only exceptions are aminopyridines and acetazolamide which can be beneficial in the treatment of downbeat nystagmus and episodic ataxias.

Authors: Timmann, D Ilg, Winfried

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: In Book

Abstract:

Background: Telemedicine interventions support behavioral state-of-the-art treatment of obsessive-compulsive disorder (OCD) as therapy can be delivered in the patients' home environment, allowing for more ecologically valid symptom actualization and access to experts even in rural areas. Sensors to indicate a patient´s emotional state and gaze direction during exposures with response prevention help to adapt therapy individually and to prevent avoidance behavior. This study will investigate the feasibility and acceptability of sensor-based telemedical treatment for children with OCD in the home setting. Methods: We plan to develop the therapy system with 10 healthy children and 5-10 children with OCD, aged 12-18 years, and then to evaluate it by treating 20 children with OCD of the same age group in 14 weekly therapy sessions via teleconference. We will use eye trackers to record the patient´s gaze and pupillometry, while the heart rate is captured by an ECG chest belt to identify stress responses. Inertial sensors capture movements to detect behavioral patterns. An app is used to record the children's self-rated symptoms and emotional state on a daily basis. Pre- and post-study questionnaires on obsessive-compulsive symptoms, feasibility and acceptance of the therapy by children, parents and therapists will be evaluated. Conclusion: We expect this therapeutic approach to show good feasibility and significant symptom reduction, as well as improvement for psychotherapeutic interventions through direct feedback of physiological responses within therapy sessions. We will further explore the underlying mechanisms in OCD treatment before applying them to other disorders.

Authors: Klein, Carolin S. Hollmann, Karsten K\"uhnhausen, Jan Alt, Annika K. Pascher, Anja Ilg, Winfried; Thierfelder, Annika; Giese, Martin A.; Passon, Helene Ernst, Christian Matthias Kasneci, Enkelejda Severitt, Björn Holderried, Martin Bethge, Wolfgang Lautenbacher, Heinrich Wörz, Ursula Primbs, Jonas Menth, Michael Gawrilow, Caterina Conzelmann, Annette Barth, Gottfried M. Renner, Tobias J.

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Technical Report

Institution: SSRN

Type of Publication: preprint

Abstract:

In this manuscript, we describe the soft- and hardware architecture as well as the implementation of a modern Internet of Medical Things (IoMT) system for sensor-assisted telepsychotherapy. It enables telepsychotherapy sessions in which the patient exercises therapy-relevant behaviors in their home environment under the remote supervision of the therapist. Wearable sensor information (electrocardiogram (ECG), movement sensors, and eye tracking) is streamed in real time to the therapist to deliver objective information about specific behavior-triggering situations and the stress level of the patients. We describe the IT infrastructure of the system which uses open standards such as WebRTC and OpenID Connect (OIDC). We also describe the system’s security concept, its container-based deployment, and demonstrate performance analyses. The system is used in the ongoing study SSTeP-KiZ (smart sensor technology in telepsychotherapy for children and adolescents with obsessive-compulsive disorder) and shows sufficient technical performance.

Authors: Primbs, Jonas Ilg, Winfried; Thierfelder, Annika; Severitt, Björn Hohnecker, Carolin Sarah Alt, Annika Kristin Pascher, Anja Wörz, Ursula Lautenbacher, Heinrich Hollmann, Karsten Barth, Gottfried Maria Renner, Tobias Menth, Michael

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Abstract:

In Hereditary Spastic Paraplegia (HSP) type 4 (SPG4) a length-dependent axonal degeneration in the cortico-spinal tract leads to progressing symptoms of hyperreflexia, muscle weakness, and spasticity of lower extremities. Even before the manifestation of spastic gait, in the prodromal phase, axonal degeneration leads to subtle gait changes. These gait changes – depicted by digital gait recording – are related to disease severity in prodromal and early-to-moderate manifest SPG4 subjects. We hypothesize that dysfunctional neuro-muscular mechanisms such as hyperreflexia and muscle weakness explain these disease severity-related gait changes of prodromal and early-to-moderate manifest SPG4 subjects. We test our hypothesis in computer simulation with a neuro-muscular model of human walking. We introduce neuro-muscular dysfunction by gradually increasing sensory-motor reflex sensitivity based on increased velocity feedback and gradually increasing muscle weakness by reducing maximum isometric force. By increasing hyperreflexia of plantarflexor and dorsiflexor muscles, we found gradual muscular and kinematic changes in neuro-musculoskeletal simulations that are comparable to subtle gait changes found in prodromal SPG4 subjects. Predicting kinematic changes of prodromal and early-to-moderate manifest SPG4 subjects by gradual alterations of sensory-motor reflex sensitivity allows us to link gait as a directly accessible performance marker to emerging neuro-muscular changes for early therapeutic interventions.

Authors: Laßmann, Christian; Ilg, Winfried; Rattay, Tim W. Schöls, Ludger Giese, Martin A.; Haeufle, Daniel

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Abstract:

Measures of step variability and body sway during gait have shown to correlate with clinical ataxia severity in several cross-sectional studies. However, to serve as a valid progression biomarker, these gait measures have to prove their sensitivity to robustly capture longitudinal change, ideally within short time-frames (e.g. one year). We present the first multi-center longitudinal gait analysis study in spinocerebellar ataxias (SCAs). We performed a combined cross-sectional (n=28) and longitudinal (1-year interval, n=17) analysis in SCA3 subjects (including 7 pre-ataxic mutation carriers). Longitudinal analysis revealed significant change in gait measures between baseline and 1-year follow-up, with high effect sizes (stride length variability: p=0.01, effect size rprb=0.66; lateral sway: p=0.007, rprb=0.73). Sample size estimation for lateral sway reveals a required cohort size of n=43 for detecting a 50% reduction of natural progression, compared to n=240 for the clinical ataxia score SARA. These measures thus present promising motor biomarkers for upcoming interventional studies.

Authors: Ilg, Winfried; M\"uller, Björn Faber, Jennifer van Gaalen, Judith Hengel, Holger Vogt, Ina R. Hennes, Guido van de Warrenburg, Bart Klockgether, Thomas Schöls, Ludger Synofzik, Matthis

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Abstract:

Background: In hereditary spastic paraplegia type 4 (SPG4), subclinical gait changes might occur years before patients realize gait disturbances. The prodromal phase of neurodegenerative disease is of particular interest to halt disease progression by future interventions before impairment has manifested. Objectives: Identification of specific movement abnormalities before manifestation of gait impairment and quantification of disease progression in the prodromal phase. Methods: 70 subjects participated in gait assessment, including 30 prodromal SPAST mutation carriers, 17 patients with mild-to-moderate manifest SPG4, and 23 healthy controls. Gait was assessed by an infrared-camera-based motion capture system to analyze features like range of motion and continuous angle trajectories. Those features were correlated with disease severity as assessed by the Spastic Paraplegia Rating Scale (SPRS) and neurofilament light chain (NfL) as a fluid biomarker indicating neurodegeneration. Results: Compared to healthy controls, we found an altered gait pattern in prodromal mutation carriers during the swing phase in segmental angles of the lower leg (p

Authors: Laßmann, Christian; Ilg, Winfried; Schneider, Marc Völker, Maximilian Haeufle, Daniel Sch\"ule, Rebecca Giese, Martin A.; Synofzik, Matthis Schöls, Ludger Rattay, Tim W.

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Abstract:

Measures of step variability and body sway during gait have shown to correlate with clinical ataxia severity in several cross-sectional studies. However, to serve as a valid progression biomarker, these gait measures have to prove their sensitivity to robustly capture longitudinal change, ideally within short time-frames (e.g. one year). We present the first multi-center longitudinal gait analysis study in spinocerebellar ataxias (SCAs). We performed a combined cross-sectional (n=28) and longitudinal (1-year interval, n=17) analysis in SCA3 subjects (including 7 pre-ataxic mutation carriers). Longitudinal analysis revealed significant change in gait measures between baseline and 1-year follow-up, with high effect sizes (stride length variability: p=0.01, effect size rprb=0.66; lateral sway: p=0.007, rprb=0.73). Sample size estimation for lateral sway reveals a required cohort size of n=43 for detecting a 50% reduction of natural progression, compared to n=240 for the clinical ataxia score SARA. These measures thus present promising motor biomarkers for upcoming interventional studies.

Authors: Ilg, Winfried; M\"uller, Björn Faber, Jennifer van Gaalen, Judith Hengel, Holger Vogt, Ina R. Hennes, Guido van de Warrenburg, Bart Klockgether, Thomas Schoels, Ludger Synofzik, Matthis

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: In Collection

Publisher: MedRxiv Preprint

Month: March

Authors: Vogel, Adam P. Magee, Michelle Torres-Vega, Reidenis Medrano-Montero, Jacqueline Cyngler, Melissa P. Kruse, Megan Rojas, Sandra Cubillos, Sebastian Contreras Canento, Tamara Maldonado, Fernanda Vazquez-Mojena, Yaimee Ilg, Winfried; Rodríguez-Labrada, Roberto Velázquez-Pérez, Luis Synofzik, Matthis

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Authors: Steiner, K. M. Thier, W. Batsikadze, G. Ludolph, N. Ilg, Winfried; Timmann, D.

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Authors: Salatiello, Alessandro; Giese, Martin A.

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: In Collection

Authors: Fleszar, Z Mellone, S Giese, Martin A.; Tacconi, C Becker, C Schöls, L Synofzik, M Ilg, Winfried

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Authors: Ludolph, Nicolas Giese, Martin A.; Mueller, Oliver M. Goericke, Sophia L. Ernst, Thomas Timmann, Dagmar Ilg, Winfried

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: In Collection

Authors: Steiner, Katharina Marie Thier, Wiebke Enders, Anne Ludolph, Nicolas Ilg, Winfried; Timmann, Dagmar

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: In Collection

Authors: Goldberg, Hagar Christensen, Andrea Flash, Tamar Giese, Martin A.; Malach, Rafael

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article

Authors: Ilg, Winfried; Golla, Heidrun Giese, Martin A.

Research Areas: Clinical Movement Control and real-life Behavior Analysis for Assistive Systems

Type of Publication: Article