Publications

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.

OBJECTIVES: With disease-modifying drugs for degenerative ataxias on the horizon, ecologically valid measures of motor performance that can detect patient-relevant changes in short, trial-like time frames are highly warranted. In this 2-year longitudinal study, we aimed to unravel and evaluate measures of ataxic gait which are sensitive to longitudinal changes in patients{\textquoteright} real life by using wearable sensors. METHODS: We assessed longitudinal gait changes of 26 participants with degenerative cerebellar disease (SARA:9.4{\textpm}4.1) at baseline, 1-year and 2-year follow-up assessment using 3 body-worn inertial sensors in two conditions: (1) laboratory-based walking (LBW); (2) real-life walking (RLW) during everyday living. In the RLW condition, a context-sensitive analysis was performed by selecting comparable walking bouts according to macroscopic gait characteristics, namely bout length and number of turns within a two-minute time interval. Movement analysis focussed on measures of spatio-temporal variability, in particular stride length variability, lateral step deviation, and a compound measure of spatial variability (SPCmp). RESULTS: Gait variability measures showed high test-retest reliability in both walking conditions (ICC \> 0.82). Cross-sectional analyses revealed high correlations of gait measures with ataxia severity (SARA, effect size ρ >= 0.75); and in particular with patients{\textquoteright} subjective balance confidence (ABC score, ρ>=0.71), here achieving higher effect sizes for real-life than lab-based gait measures (e.g. SPCmp: RLW ρ=0.81 vs LBW ρ=0.71). While the clinician-reported outcome SARA showed longitudinal changes only after two years, the gait measure SPCmp revealed changes already after one year with high effect size (rprb=0.80). In the subgroup with spinocerebellar ataxia type 1, 2 or 3 (SCA1/2/3), the effect size was even higher (rprb=0.86). Based on these effect sizes, sample size estimation for the gait measure SPCmp showed a required cohort size of n=42 participants (n=38 for SCA1/2/3 subgroup) for detecting a 50\% reduction of natural progression after one year by a hypothetical intervention, compared to n=254 for the SARA. CONCLUSIONS: Gait variability measures revealed high reliability and sensitivity to longitudinal change in both laboratory-based constrained walking as well as in real-life walking. Due to their ecological validity and larger effect sizes, characteristics of real-life gait recordings are promising motor performance measures as outcomes for future treatment trials.Competing Interest StatementDr Ilg received consultancy honoraria by Ionis Pharmaceuticals, unrelated to the present work. Mr Seemann reports no disclosures. Mrs Beyme reports no disclosures. Mrs John reports no disclosures. Mr Harmuth reports no disclosures. Prof Giese reports no disclosures. Prof Schoels served as advisor for Alexion, Novartis and Vico. He participates as a principal investigator in clinical studies sponsored by Vigil Neuroscience (VGL101-01.001; VGL101-01.002), Vico Therapeutics (VO659-CT01), PTC Therapeutics (PTC743-NEU-003-FA) and Stealth BioTherapeutics (SPIMD-301), all unrelated to the present work. Prof Timmann reports no disclosures. Prof Synofzik has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Biogen, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra, Lilly, and Solaxa, all unrelated to the present manuscript. Funding StatementThis 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. and M.G.). as well as the Else Kroener-Fresenius Stiftung Clinician Scientist program PRECISE.net (to M.S.). In addition, this work was supported by the European Union, project European Rare Disease Research Alliance (ERDERA, $\#$ 101156595) (to M.S.).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 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).Yes I 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 and its Supplementary material. Raw data regarding human participants (e.g. clinical data) are not shared freely to protect the privacy of the human participants involved in this study; no consent for open sharing has been obtained.

Social interaction is crucial for survival in primates. For the study of social vision in monkeys, highly controllable macaque face avatars have recently been developed, while body avatars with realistic motion do not yet exist. Addressing this gap, we developed a pipeline for three-dimensional motion tracking based on synchronized multi-view video recordings, achieving sufficient accuracy for life-like full-body animation. By exploiting data-driven pose estimation models, we track the complete time course of individual actions using a minimal set of hand-labeled keyframes. Our approach tracks single actions more accurately than existing pose estimation pipelines for behavioral tracking of non-human primates, requiring less data and fewer cameras. This efficiency is also confirmed for a state-of-the-art human benchmark dataset. A behavioral experiment with real macaque monkeys demonstrates that animals perceive the generated animations as similar to genuine videos, and establishes an uncanny valley effect for bodies in monkeys.Competing Interest StatementThe authors have declared no competing interest.

Primates, as social beings, have evolved complex brain mechanisms to navigate intricate social environments. This review explores the neural bases of body perception in both human and nonhuman primates, emphasizing the processing of social signals conveyed by body postures, movements, and interactions. Early studies identified selective neural responses to body stimuli in macaques, particularly within and ventral to the superior temporal sulcus (STS). These regions, known as body patches, represent visual features that are present in bodies but do not appear to be semantic body detectors. They provide information about posture and viewpoint of the body. Recent research using dynamic stimuli has expanded the understanding of the body-selective network, highlighting its complexity and the interplay between static and dynamic processing. In humans, body-selective areas such as the extrastriate body area (EBA) and fusiform body area (FBA) have been implicated in the perception of bodies and their interactions. Moreover, studies on social interactions reveal that regions in the human STS are also tuned to the perception of dyadic interactions, suggesting a specialized social lateral pathway. Computational work developed models of body recognition and social interaction, providing insights into the underlying neural mechanisms. Despite advances, significant gaps remain in understanding the neural mechanisms of body perception and social interaction. Overall, this review underscores the importance of integrating findings across species to comprehensively understand the neural foundations of body perception and the interaction between computational modeling and neural recording.

Abstract Objective Voluntary upper limb movements are an ecologically important yet insufficiently explored digital-motor outcome domain for trials in degenerative ataxia. We extended and validated the trial-ready quantitative motor assessment battery “Q-Motor” for upper limb movements with clinician-reported, patient-focused, and performance outcomes of ataxia. Methods Exploratory single-center cross-sectional assessment in 94 subjects (46 cross-genotype ataxia patients; 48 matched controls), comprising five tasks measured by force transducer and/or position field: Finger Tapping, diadochokinesia, grip-lift, and—as novel implementations—Spiral Drawing, and Target Reaching. Digital-motor measures were selected if they discriminated from controls (AUC >0.7) and correlated—with at least one strong correlation (rho ≥0.6)—to the Scale for the Assessment and Rating of Ataxia (SARA), activities of daily living (FARS-ADL), and the Nine-Hole Peg Test (9HPT). Results Six movement features with 69 measures met selection criteria, including speed and variability in all tasks, stability in grip-lift, and efficiency in Target Reaching. The novel drawing/reaching tasks best captured impairment in dexterity (|rho9HPT| ≤0.81) and FARS-ADL upper limb items (|rhoADLul| ≤0.64), particularly by kinematic analysis of smoothness (SPARC). Target hit rate, a composite of speed and endpoint precision, almost perfectly discriminated ataxia and controls (AUC: 0.97). Selected measures in all tasks discriminated between mild, moderate, and severe impairment (SARA upper limb composite: 0–2/>2–4/>4–6) and correlated with severity in the trial-relevant mild ataxia stage (SARA ≤10, n = 20). Interpretation Q-Motor assessment captures multiple features of impaired upper limb movements in degenerative ataxia. Validation with key clinical outcome domains provides the basis for evaluation in longitudinal studies and clinical trial settings.

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.

The inverse kinematics (IK) problem addresses how both humans and robotic systems coordinate movement to resolve redundancy, as in the case of arm reaching where more degrees of freedom are available at the joint versus hand level. This work focuses on which coordinate frames best represent human movements, enabling the motor system to solve the IK problem in the presence of kinematic redundancies. We used a multi-dimensional sparse source separation method to derive sets of basis (or source) functions for both the task and joint spaces, with joint space represented by either absolute or anatomical joint angles. We assessed the similarities between joint and task sources in each of these joint representations, finding that the time-dependent profiles of the absolute reference frame’s sources show greater similarity to corresponding sources in the task space. This result was found to be statistically significant. Our analysis suggests that the nervous system represents multi-joint arm movements using a limited number of basis functions, allowing for simple transformations between task and joint spaces. Additionally, joint space seems to be represented in an absolute reference frame to simplify the IK transformations, given redundancies. Further studies will assess this finding’s generalizability and implications for neural control of movement.

For social species, e.g., primates, the perceptual analysis of social interactions is an essential skill for survival, emerging already early during development. While real-life emotional behavior includes predominantly interactions between conspecifics, research on the perception of emotional body expressions has primarily focused on perception of single individuals. While previous studies using point-light or video stimuli of interacting people suggest an influence of social context on the perception and neural encoding of interacting bodies, it remains entirely unknown how emotions of multiple interacting agents are perceptually integrated. We studied this question using computer animation by creating scenes with two interacting avatars whose emotional style was independently controlled. While participants had to report the emotional style of a single agent, we found a systematic influence of the emotion expressed by the other, which was consistent with the social interaction context. The emotional styles of interacting individuals are thus jointly encoded.