Objective: The diagnostic work-up for vestibular pathologies involves a battery of tests designed to quantify the functioning of the otolith organs and semicircular canals. Clinical data from video head-impulse tests, vestibular-evoked myogenic potentials, subjective visual verticality, and caloric tests are usually collected. Our study applied regression analyses to predict the affected side of a patient group with vestibular schwannoma, learning from laboratory vestibular tests, to assess their relative predictive capacity in predicting the tumor side. Technology or Method: The dataset was pre-processed to handle missing values, outliers, and differences in the measurement scales. The mean asymmetry values and their direction (either negative = left-side asymmetry or positive = right-side asymmetry) were calculated. The classifiers’ ability to accurately predict the tumor side was evaluated. Finally, both logistic and multiple regression analyses were conducted. Results: The regression models’ binary output (i.e., right or left side affected) was compared to the true labels of the affected side given by magnetic resonance imaging to estimate the model’s accuracy. Linear regression analysis showed that caloric, cVEMP and RLLL reached AUCs >0.9; multiple regression revealed an AUC of 0.96 for caloric and cVEMP combined. Conclusion: Our study demonstrated that combining caloric and vestibular-evoked myogenic potential tests provides the most accurate identification of the vestibular schwannoma-affected side, achieving the highest predictive capacity. Furthermore, our findings align with previous studies revealing that the monocular video head-impulse test introduces a gain bias for all three semicircular canals that must be adjusted to correctly estimate semicircular canal function. Clinical and Impact—This study addresses the clinical challenge of finding the affected side in unilateral vestibular schwannoma patients by using machine learning to vestibular tests linking computational methods with clinical practice

BACKGROUND/OBJECTIVES:Dizziness is highly prevalent in patients with concussion, with a significant proportion of these patients experiencing visually induced dizziness (VID) in complex visual environments. As current diagnoses rely primarily on subjective questionnaires, establishing objective diagnostic frameworks remains a challenge. This study aimed to quantify responses to optokinetic stimulation to explore potential clinical subtypes based on objective postural and subjective symptom measures. METHODS:Concussed patients and healthy controls underwent optokinetic stimulation, with patients stratified into High and Low VVAS groups by the median Visual Vertigo Analogue Scale (VVAS) score. Induced postural metrics and symptoms were statistically compared and modelled to establish a framework for subtype classification of VID. RESULTS:Patients with High VVAS exhibited significantly greater postural instability and higher symptom scores during optokinetic stimulation than healthy controls. While mean induced postural performance and dizziness in patients with Low VVAS were comparable to healthy controls, this patient cohort demonstrated increased heterogeneity in individual responses. Regression modelling successfully distinguished patients with High VVAS from healthy controls, achieving strong diagnostic accuracy for the postural (AUC = 0.815) and symptom-based (AUC = 0.958) models. Using this diagnostic framework, distinct postural and visuoperceptual subtypes were identified within the visual-vestibular mismatch cohort. CONCLUSIONS:This study provides a robust framework for post-concussive VID by combining objective postural metrics with subjective induced symptom scales. This classification identifies distinct clinical subtypes and characterises specific manifestations to facilitate tailored rehabilitation programmes. Future research should investigate whether these findings can guide targeted and individualised programmes to optimise rehabilitation.

Die systematische klinische Untersuchung von Augenbewegungen, also Augenposition, Motilität, Blickfolge, Blickhaltefunktion und Sakkaden, ermöglicht oft eine präzise topografisch-anatomische Diagnose, d. h., ob eine Störung im Bereich von Mesencephalon, Pons, Medulla oblongata, Cerebellum oder selten Cortex vorliegt; sie ist damit wie ein Fenster in das Hirn. Vertikale Augenbewegungen werden im Bereich des Mesencephalons generiert (Kern des rostralen Fasciculus medialis longitudinalis und interstitieller Nucleus Cajal) und horizontale im Bereich der Pons (insbesondere paramediane pontine Formatio reticularis). Das Cerebellum hat eine übergeordnete Funktion: eine wichtige zerebelläre Struktur ist dabei der Flocculus. Zentrale Augenbewegungsstörungen finden sich bei diversen Erkrankungen, z. B. akuter Beginn bei Schlaganfall, subakut bei entzündlichen Erkrankungen sowie chronisch progredient bei neurodegenerativen, genetischen oder metabolischen Erkrankungen. Die Therapie richtet sich nach der zugrunde liegenden Ätiologie.

Cerebellar ataxia, neuropathy, vestibular-areflexia syndrome (CANVAS) has been linked to biallelic intronic repeat-expansions in RFC1. Video-head-impulse testing (vHIT) offers a quantitative assessment of the angular vestibulo-ocular reflex (aVOR) of all three canals. We evaluated patterns of peripheral-vestibular impairment, its change over time and evaluated correlations with other parameters. PubMed/Embase were searched for articles reporting vHIT in patients with CANVAS/RFC1-related ataxia. A multiple linear-regression model was used to analyse relationships between vHIT-gains and clinical parameters (age, disease duration, sex, biallelic RFC1 expansion). A special focus was put on sequential vHIT in individual patients. 23/64 studies met inclusion criteria; additional 13 studies were identified through reference screening. Twenty-five studies reported individual vHIT-gains and demographic data, suitable for quantitative analysis. Substantial aVOR-gain reductions were found for horizontal (0.32 ± 0.02, n = 146 patients), anterior (0.39 ± 0.03, n = 27) and posterior (0.29 ± 0.03, n = 27) canals. Linear regression showed an association between horizontal vHIT-gains (n = 146 patients; range of gain: 0-1.3) and disease duration (range: 0–444 months, coef. =-0.0048, p = 0.031) and male sex (coef. =-0.1604, p < 0.001). A decline in horizontal-canal vHIT-gains at least one side over time was noted in 15/21 patients after a mean follow-up time of 33.4 ± 10.7 months. vHIT is a potential biomarker for monitoring progression of CANVAS/RFC1-related ataxia. The significant association between reduced vHIT-gains and disease duration, and their intra-individual decline over time emphasize that impairment of the aVOR reflects the underlying neurodegenerative disease process. Multi-centre prospective studies are needed for systematic early screening and longitudinal validation as outcome for future targeted therapy trials.

Background/Objectives: The auditory middle-latency responses (AMLRs) assess central sensory processing beyond the brainstem and serve as a measure of sensory gating. They have clinical relevance in the diagnosis of neurological conditions. In this study, magnitude and habituation of the AMLRs were tested for sensitivity and specificity in classifying dizzy patients with vestibular migraine (VM) and post-concussive syndrome. Methods: Twenty-three healthy individuals, 12 concussion and 26 VM patients were recruited. AMLR were recorded performing five blocks of 200 binaural click-stimulations at 60 dB sensation level with a repetition rate of 6.1 Hz. Reduction in P0, Na and Pa magnitudes between blocks was measured. Group classifications were performed through logistic and multiple regression. Results: Among healthy subjects, a consistent P0 and Na habituation can be observed. Concussed subjects show control-like Na habituation, despite a lower magnitude, while P0 habituation was negligible. VM patients showed poor habituation for all waves. Regression analyses suggest that P0 and Na better distinguish healthy subjects from neurological patients, whereas Pa best distinguishes concussion from VM patients. Conclusions: The results support that AMLR habituation can contribute to unraveling different mechanisms of dizziness due to concussion compared to VM, providing insights that can complement routine diagnostic assessments.

Purpose: Accurate and precise navigation in space and postural stability rely on the central integration of multisensory input (vestibular, proprioceptive, visual), weighted according to its reliability, to continuously update the internal estimate of the direction of gravity. In this study, we examined both peripheral and central vestibular functions in a world-renowned 53-year-old male tightrope walker and investigated the extent to which his exceptional performance was reflected in our findings. Methods: Comprehensive assessments were conducted, including semicircular canal function tests (caloric irrigation, rotatory-chair testing, video head impulse testing of all six canals, dynamic visual acuity) and otolith function evaluations (subjective visual vertical, fundus photography, ocular/cervical vestibular-evoked myogenic potentials [oVEMPs/cVEMPs]). Additionally, static and dynamic posturography, as well as video-oculography (smooth-pursuit eye movements, saccades, nystagmus testing), were performed. The participant’s results were compared to established normative values. High-resolution diffusion tensor magnetic resonance imaging (DT-MRI) was utilized to assess motor tract integrity. Results: Semicircular canal testing revealed normal results except for a slightly reduced response to right-sided caloric irrigation (26% asymmetry ratio; cut-off = 25%). Otolith testing, however, showed marked asymmetry in oVEMP amplitudes, confirmed with two devices (37% and 53% weaker on the left side; cut-off = 30%). Bone-conducted cVEMP amplitudes were mildly reduced bilaterally. Posturography, video-oculography, and subjective visual vertical testing were all within normal ranges. Diffusion tensor MRI revealed no structural abnormalities correlating with the observed functional asymmetry. Conclusions: This professional tightrope walker’s exceptional balance skills contrast starkly with significant peripheral vestibular (otolithic) deficits, while MR imaging, including diffusion tensor imaging, remained normal. These findings highlight the critical role of central computational mechanisms in optimizing multisensory input signals and fully compensating for vestibular asymmetries in this unique case.

Self-motion perception relies on the central integration of vestibular, visual and proprioceptive sensory inputs into a coherent percept of self-motion. To better understand the central integration of linear and rotational stimuli, we examined rotational and translational movements in the horizontal plane in healthy subjects (HS) and in patients with unilateral vestibular hypofunction (pwUVH). We established a novel heading discrimination paradigm using a motion platform to examine heading direction perception for translational movements with additional yaw rotations of - 1°, 0°, or 1°. We examined 26 HS and 26 pwUVH. Heading direction perception in HS and pwUVH was strongly driven by rotational stimuli. Among HS, adding 1° of yaw rotation to a translational movement resulted in an average shift of perceived straight-ahead translations to the opposite side of 2.15° (yaw to the right) and 2.30° (yaw to the left) respectively. pwUVH showed significantly higher discrimination thresholds (right UVH +3.3°, left UVH +6.4°) across all conditions than HS. We show that vestibular guided self-motion perception is strongly influenced by rotational movements, supporting central canal-otolith integration hypothesis. Self-motion perception is significantly impaired towards both sides in patients with unilateral vestibular hypofunction.

Bei einem Nystagmus handelt es sich um periodische, meist unwillkürliche Augenbewegungen mit einer meist langsamen Augendrift und einer schnellen Rückstellphase. Leitsymptome können verschwommen Sehen, reduzierter Visus, Schwank-, Drehschwindel und/oder Gangstörungen sein. Die Diagnose beruht auf der Beschreibung von Form, Richtung (die nach der schnellen Phase angegeben wird) sowie auslösenden/modulierenden Faktoren. Häufige Formen sind peripherer oder zentraler Spontannystagmus sowie Blickrichtungs-, Lagerungs-, Kopfschüttel- und Rebound-Nystagmus; daneben gibt es Nystagmus-ähnliche Formen, wie Sakkadische Intrusionen. Ein Spontannystagmus ist definiert als ein in Primärposition ohne Provokationsmanöver vorhandener Nystagmus. Es kann sich um einen peripheren vestibulären Spontannystagmus, z. B. bei akuter unilateraler Vestibulopathie, oder zentrale Formen wie Downbeat- oder Upbeat-Nystagmus handeln. Therapie bei den beiden letzteren ist 4-Aminopyridin.

Concussion, or mild traumatic brain injury, is caused by sudden mechanical forces impacting the brain either directly or through inertial loading. This can lead to physical, behavioural and cognitive impairments. Despite concussion being a significant health issue, our understanding of the relationship between initial impact force and the subsequent neurological consequences is not well understood. Previously, we established a model of concussion in zebrafish larvae. Here, we further investigate concussions of varying severities in zebrafish larvae using linear deceleration. Using an acoustic assay to monitor the larval sensorimotor behaviour, we found that different parameters of the resulting escape behaviour are modulated by the impact force of the preceding concussive insult. To investigate the relative contributions of habituation performance and fatigue on the escape response behaviour, we constructed a neurocomputational model. Our findings suggest that a concussive impact initially affects habituation performance at first and, as the impact force increases, fatigue is induced. Fatigue then alters the escape response behaviour in an opposing manner.

ZUSAMMENFASSUNGDer Diagnose von Augenbewegungsstörungen und der Nystagmusformen beruht auf einer systematischen klinischen Untersuchung aller Arten von Augenbewegungen. Diese Untersuchung umfasst: Augenposition, Untersuchung auf einen Spontannystagmus, Motilität, Blickfolge, Blickhaltefunktion, Sakkaden, Vergenzreaktion, optokinetischer Nystagmus, Funktion des vestibulookulären Reflexes (VOR) sowie die Fixationssuppression des VOR. Anatomisch relevante Strukturen sind Mesenzephalon, Pons, Medulla oblongata, Zerebellum und Kortex. Topografisch anatomisch gelten die einfachen klinischen Regeln: Vertikale und torsionale Augenbewegungen werden vorwiegend im Mesenzephalon und horizontale Augenbewegungen in dem Pons generiert. Typische Zeichen einer Mittelhirnläsion sind vertikale Sakkaden- oder Blickparese, ein isolierter vertikaler Blickrichtungsnystagmus und einer Ponsläsion entsprechende horizontale Störungen. Das Zerebellum spielt eine Rolle bei praktisch allen Augenbewegungen; typische klinische Zeichen sind eine allseitige Blickfolgesakkadierung, Blickrichtungsnystagmus oder dysmetrische Sakkaden.Unter einem Nystagmus versteht man rhythmische Augenbewegungen, die in der Regel aus einem langsamen (ursächlichen bzw. pathologischen) Augendrift und einer schnellen kompensatorischen Rückstellbewegung (Rückstellsakkade) bestehen. Es lassen sich 3 einfache Kategorien unterscheiden: Spontannystagmus, d. h. ein Nystagmus, der bei Fixation in Geradeaus-Blickposition auftritt, Nystagmusformen, die nur in Abhängigkeit von der Blickrichtung auftreten und Nystagmen, die nur durch bestimmte Manöver ausgelöst werden: Kopfschütteln, Lagerung, Hyperventilation oder physikalischen Druck (z. B. Pressen). Letztere sind oft durch peripher-vestibuläre Läsionen ausgelöst, können aber auch zentralen Ursprungs sein. Viele zentrale Nystagmusformen erlauben eine genaue anatomische Lokalisation, z. B. der Downbeat-Nystagmus (DBN), der meistens auf einer Flocculus-Läsion beruht oder der Upbeat-Nystagmus (UBN) auf einer Läsion im Mesencephalon oder der Medulla oblongata. Beispiele einer Pharmakotherapie sind die Gabe von 4-Aminopyridin beim DBN und UBN, Memantin oder Gabapentin beim Fixationspendelnystagmus oder Baclofen beim periodisch-alternierenden Nystagmus.

BACKGROUND AND OBJECTIVES:We developed repetitive ocular vestibular-evoked myogenic potentials (roVEMP) as an electrophysiologic test that allows us to elicit the characteristic decrement of extraocular muscles in patients with ocular myasthenia gravis (OMG). Case-control studies demonstrated that roVEMP reliably differentiates patients with OMG from healthy controls. We now aimed to evaluate the diagnostic accuracy of roVEMP for OMG diagnosis in patients with ptosis and/or diplopia. METHODS:In this blinded prospective diagnostic accuracy trial, we compared roVEMP in 89 consecutive patients presenting with ptosis and/or diplopia suspicious of OMG with a multimodal diagnostic approach, including clinical examination, antibodies, edrophonium testing, repetitive nerve stimulation of accessory and facial nerves, and single-fiber EMG (SFEMG). We calculated the roVEMP decrement as the ratio between the mean of the first 2 responses compared with the mean of the sixth-ninth responses in the train and used cutoff of >9% (unilateral decrement) in a 30 Hz stimulation paradigm. RESULTS:Following a complete diagnostic work-up, 39 patients (44%) were diagnosed with ocular MG, while 50 patients (56%) had various other neuro-ophthalmologic conditions, but not MG (non-MG). roVEMP yielded 88.2% sensitivity, 30.2% specificity, 50% positive predictive value (PPV), and 76.5% negative predictive value (NPV). For comparison, SFEMG resulted in 75% sensitivity, 56% specificity, 55.1% PPV, and 75.7% NPV. All other diagnostic tests (except for the ice pack test) also yielded significantly higher positive results in patients with MG compared with non-MG. DISCUSSION:The study revealed a high sensitivity of 88.2% for roVEMP in OMG, but specificity and PPV were too low to allow for the OMG diagnosis as a single test. Thus, differentiating ocular MG from other neuro-ophthalmologic conditions remains challenging, and the highest diagnostic accuracy is still obtained by a multimodal approach. In this study, roVEMP can complement the diagnostic armamentarium for the diagnosis of MG. CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that in patients with diplopia and ptosis, roVEMP alone does not accurately distinguish MG from non-MG disorders. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov: NCT03049956.

The diagnosis of ocular motor disorders and the different forms of a nystagmus is based on a systematic clinical examination of all types of eye movements: eye position, spontaneous nystagmus, range of eye movements, smooth pursuit, saccades, gaze-holding function, vergence, optokinetic nystagmus, as well as testing of the function of the vestibulo ocular reflex (VOR) and visual fixation suppression of the VOR. Relevant anatomical structures are the midbrain, pons, medulla, cerebellum, and cortex. There is a simple clinical rule: vertical and torsional eye movements are generated in the midbrain, horizontal in the pons. The cerebellum is relevant for almost all types of eye movements; typical pathological findings are saccadic smooth pursuit, gaze-evoked nystagmus or dysmetric saccades.Nystagmus is defined as a rhythmic, most often involuntary eye movement. It normally consists of a slow (pathological) drift of the eyes and a fast central compensatory movement of the eyes back to the primary position (re-fixation saccade). There are three major categories: first, spontaneous nystagmus, i. e. nystagmus which occurs in the gaze straight ahead position as upbeat or downbeat nystagmus; second, nystagmus that becomes visible at eccentric gaze only and third, nystagmus which can be elicited by certain maneuvers, e. g. head-shaking, head positioning, air pressure or hyperventilation, most of which are of peripheral vestibular origin. The most frequent central types of spontaneous nystagmus are downbeat and upbeat, infantile, pure torsional, pendular fixation, periodic alternating, and seesaw nystagmus. Many types of central nystagmus allow a precise neuroanatomical localization: for instance, downbeat nystagmus, which is most often caused by a bilateral floccular lesion or dysfunction, or upbeat nystagmus, which is caused by a lesion in the mesencephalon or medulla oblongata. Examples of pharmacotherapy are the use of 4-aminopyridine for downbeat and upbeat nystagmus, memantine or gabapentin for fixation pendular nystagmus or baclofen for periodic alternating nystagmus.

A feasible, inexpensive, rapid, and easy-to-use method to measure vestibular vertical movement perception is needed to assess the sacculus-mediated low-frequency otolith function of dizzy patients. To evaluate the feasibility of reaction time assessment in response to vertical motion induced by an elevator in healthy young individuals. We recorded linear acceleration/deceleration reaction times (LA-RT/LD-RT) of 20 healthy (13 female) subjects (mean age: 22 years ± 1 SD) as a measure of vertical vestibular motion perception. LA-RT/LD-RT were defined as the time elapsed from the start of elevator acceleration or deceleration to the time at which subjects in a sitting position indicated perceiving a change in velocity by pushing a button with their thumb. The light reaction time was measured as a reference. All 20 subjects tolerated the assessment with repeated elevator rides and reported no adverse events. Over all experiments, one upward and four downward rides had to be excluded for technical reasons (2.5%). The fraction of premature button presses varied among the four conditions, possibly related to elevator vibration (upward rides: LA-RT-up 66%, LD-RT-up 0%; downward rides: LA-RT-down 12%, LD-RT-down 4%). Thus LD-RT-up yielded the most robust results. The reaction time to earth-vertical deceleration elicited by an elevator provides a consistent indicator of linear vestibular motion perception in healthy humans. The testing procedure is inexpensive and easy to use. Deceleration on upward rides yielded the most robust measurements.

A mild traumatic brain injury is a neurological disturbance of transient or/and chronic nature after a direct blow of the head/neck or exposure of the body to impulsive biomechanical forces, indirectly affecting the brain. The neuropathological events leading to the clinical signs, symptoms and functional disturbances are still elusive due to a lack of sensitive brain-screening tools. Animal models offer the potential to study neural pathomechanisms in close detail. We recently proposed a non-invasive protocol for inducing concussion-like symptoms in larval zebrafish via exposure to rapid linearly accelerating-decelerating body motion. By mean of auditory 'startle reflex habituation' assessments-an established neurophysiological health index-we probed acute and chronic effects that mirror human concussion patterns. This study aimed at expanding our previous work by assessing the ensuing effects with visual-as opposed to auditory-'startle reflex habituation' quantifications, by using the same methodology. We observed that immediately after impact exposure, the fish showed impaired sensory reactivity and smaller decay constant, possibly mirroring acute signs of confusion or loss of consciousness in humans. By 30-min post-injury, the fish display temporary signs of visual hypersensitivity, manifested as increased visuomotor reactivity and a relatively enlarged decay constant, putatively reflecting human post-concussive sign of visual hypersensitivity. In the following 5-24 h, the exposed fish progressively develop chronic signs of CNS dysfunction, in the form of low startle responsivity. However, the preserved decay constant suggests that neuroplastic changes may occur to restore CNS functioning after undergoing the 'concussive procedure'. The observed findings expand our previous work providing further behavioural evidence for the model. Limitations that still require addressment are discussed, advancing further behavioural and microscopic analyses that would be necessary for the validation of the model in its putative relatability with human concussion. This work aimed at reproducing a mild head trauma in larval zebrafish through a non-invasive biomechanical method employing rapidly accelerating-decelerating linear movements. Through quantifications of light-induced startle reflex locomotor distance travelled and habituation, Beppi et al. showed transient and long-term neurophysiological changes that warrant further neuropathological investigation.

Thus, this research topic aimed to bring together new insights into the clinical utility of 51 quantitative vestibular testing, focusing on current state-of-the-art technologies as the vHIT and 52VEMPs. A highlight of this article collection series of manuscripts discuss various 53 factors that may influence the aVOR as recorded the vHIT. In an in-depth review, the use 54 and the interpretation of vHIT-results in the clinical setting are critically discussed, focusing on 55 the geometrical basis and the underlying principles when collecting (

Objective The aim of the present study was to identify patients who developed acute unilateral peripheral vestibulopathy (AUPVP) after COVID-19 vaccination. Methods For this single-center, retrospective study, we screened the medical records of our tertiary interdisciplinary neurotology center for patients who had presented with AUPVP within 30 days after COVID-19 vaccination (study period: 1 June−31 December 2021). The initial diagnosis of AUPVP was based on a comprehensive bedside neurotological examination. Laboratory vestibular testing (video head impulse test, cervical and ocular vestibular evoked myogenic potentials, dynamic visual acuity, subjective visual vertical, video-oculography, caloric testing) was performed 1–5 months later. Results Twenty-six patients were diagnosed with AUPVP within the study period. Of those, n = 8 (31%) had developed acute vestibular symptoms within 30 days after COVID-19 vaccination (mean interval: 11.9 days, SD: 4.8, range: 6–20) and were thus included in the study. The mean age of the patients (two females, six males) was 46 years (SD: 11.7). Seven patients had received the Moderna mRNA vaccine and one the Pfizer/BioNTech mRNA vaccine. All patients displayed a horizontal(-torsional) spontaneous nystagmus toward the unaffected ear and a pathological clinical head impulse test toward the affected ear on initial clinical examination. Receptor-specific laboratory vestibular testing performed 1–5 months later revealed recovery of vestibular function in two patients, and heterogeneous lesion patterns of vestibular endorgans in the remaining six patients. Discussion and Conclusions The present study should raise clinicians' awareness for AUPVP after COVID-19 vaccination. The relatively high fraction of such cases among our AUPVP patients may be due to a certain selection bias at a tertiary neurotology center. Patients presenting with acute vestibular symptoms should be questioned about their vaccination status and the date of the last vaccination dose. Furthermore, cases of AUPVP occurring shortly after a COVID-19 vaccination should be reported to the health authorities to help determining a possible causal relationship.

Background: Walking impairment is a common and highly disabling symptom in people with MS (PwMS). Ambulatory deterioration is poorly characterized in PwMS and reliable prognosis that may guide clinical decisions is elusive. This study aimed to objectively track the progression of clinical walking performance and kinematic gait patterns in PwMS over 4 years, thereby revealing potential prognostic markers for deterioration of ambulatory function.Methods: Twenty-two PwMS (48.8 +/- 9.9 years, 14 females; expanded disability status scale [EDSS]: 4.5 +/- 0.9 points) with gait impairments were recruited at the University Hospital Zurich, Switzerland. Gait function was monitored over a period of 4 years using a set of standardized clinical walking tests (timed 25-foot walk [T25FW], 6 min walk test [6MWT], 12-item MS walking scale [MSWS-12]) and comprehensive 3D kinematic gait analysis. Walking decline was assessed in the full patient cohort and in patient sub-groups that were built according to MS type (relapsing-remitting [RRMS], progressive [PMS]) and subjects' pathological gait signature (cluster groups 1-3). Results: In the total cohort (n = 22), we found a significant worsening in the 6MWT (BL vs. 4y: -41.1 m; P = 0.0053), while the performance in the T25FW, MSWS-12 and the EDSS remained unchanged over 4 years. Subjects with PMS (n = 12) showed a significant worsening in the EDSS (BL vs. 4y: +0.6 points; P = 0.0053), which was not observed in participants with RRMS (n = 10). Whereas deterioration of clinical walking function was not different between subjects with RRMS and PMS, we identified differences in clinical walking deterioration between PwMS with varying gait pattern pathologies: Subjects with spastic-paretic gait impairments (cluster 1; n = 9) demonstrated a marked worsening in the T25FW (BL vs. 4y: +2 s; P = 0.0020) and 6MWT (BL vs. 4y: -92.9 m; P < 0.0001) which was not seen in PwMS with an ataxia-like (cluster 2; n = 8) or unstable walking pattern (cluster 3; n = 5). Deterioration of clinical walking performance in cluster 1 was accompanied by a specific worsening of gait deficits that were characteristic of this cluster at baseline, a phenomenon not found in the other sub-groups. Accordingly, aggravation of cluster 1-specific gait impairments over 4 years predicted deterioration of the 6MWT in the total cohort (n = 22) with an accuracy of 90.9% (sensitivity: 90.9%; specificity: 90.9%; Nagelkerkes coefficient of determination R2: 0.721), unveiling key determinants of MS-related walking decline. Conclusions: Our findings highlight the potential of quantitative, functional outcomes for objective tracking of disease progression in PwMS. Gait pattern analysis can provide valuable information on the underlying pathomechanisms of gait deterioration and may represent a complementary prognostic tool for walking function in PwMS. Clinical trial: clinicaltrials.gov, NCT01576354

A mild traumatic brain injury is a neurological dysfunction caused by biomechanical forces transmitted to the brain in physical impacts. The current understanding of the neuropathological cascade resulting in the manifested clinical signs and symptoms is limited due to the absence of sensitive brain imaging methods. Zebrafish are established models for the reproduction and study of neurobiological pathologies. However, all available models mostly recreate moderate-to-severe focal injuries in adult zebrafish. The present work has induced a mild brain trauma in larval zebrafish through a non-invasive biomechanical approach. A custom-made apparatus with a commercially available motor was employed to expose larvae to rapidly decelerating linear movements. The neurophysiological changes following concussion were assessed through behavioural quantifications of startle reflex locomotor distance and habituation metrics. Here we show that the injury was followed, within five minutes, by a transient anxiety state and CNS dysfunction manifested by increased startle responsivity with impaired startle habituation, putatively mirroring the human clinical sign of hypersensitivity to noise. Within a day after the injury, chronic effects arose, as evidenced by an overall reduced responsivity to sensory stimulation (lower amplitude and distance travelled along successive stimuli), reflecting the human post-concussive symptomatology. This study represents a step forward towards the establishment of a parsimonious (simple, less ethically concerning, yet sensitive) animal model of mild TBI. Our behavioural findings mimic aspects of acute and chronic effects of human concussion, which warrant further study at molecular, cellular and circuit levels. While our model opens wide avenues for studying the underlying cellular and molecular pathomechanisms, it also enables high-throughput testing of therapeutic interventions to accelerate post-concussive recovery.