Chronic use of cannabis might impair sensory error processing in the cerebellum through endocannabinoid dysregulation

Chronic use of cannabis leads to both motor deficits and the downregulation of CB1 receptors (CB1R) in the cerebellum. In turn, cerebellar damage is often related to impairments in motor learning and control. Further, a recent motor learning task that measures cerebellar-dependent adaptation has been shown to distinguish well between healthy subjects and chronic cannabis users. Thus, the deteriorating effects of chronic cannabis use in motor performance point to cerebellar adaptation as a key process to explain such deficits. We review the literature relating chronic cannabis use, the endocannabinoid system in the cerebellum, and different forms of cerebellar-dependent motor learning, to suggest that CB1R downregulation leads to a generalized underestimation and misprocessing of the sensory errors driving synaptic updates in the cerebellar cortex. Further, we test our hypothesis with a computational model performing a motor adaptation task and reproduce the behavioral effect of decreased implicit adaptation that appears to be a sign of chronic cannabis use. Finally, we discuss the potential of our hypothesis to explain similar phenomena related to motor impairments following chronic alcohol dependency

Relationship between intensity and recovery in post-stroke rehabilitation: a retrospective analysis.

Work in animal models suggests high-intensity rehabilitation-based training that starts soon after stroke is the most effective approach to promote recovery.1 In humans, the interaction between treatment onset and intensity remains unclear.2 It has been suggested that reducing daily treatment duration below 3 hours at the acute and subacute stages leads to a poorer prognosis,3 while there may also be an upper bound beyond which high-intensity motor rehabilitation at the acute stage might lead to unwanted side effects.4 Designing optimal rehabilitation treatment programmes for stroke patients will not be possible until we understand ‘how much’, ‘when’ and ‘what’ treatment should be delivered.2 In this retrospective analysis, we assessed patients’ responsiveness to high-intensity and low-intensity rehabilitation protocols across different stages of chronicity post-stroke to address the ‘how much’ and ‘when’ questions.This study was supported by the cRGS project under the grant agreement H2020-EU, ID: 840052, and by the RGS@home project from H2020-EU, EIT Health, ID: 19 277

Estimating upper-extremity function from kinematics in stroke patients following goal-oriented computer-based training

Introduction: After a stroke, a wide range of deficits can occur with varying onset latencies. As a result, assessing impairment and recovery are enormous challenges in neurorehabilitation. Although several clinical scales are generally accepted, they are time-consuming, show high inter-rater variability, have low ecological validity, and are vulnerable to biases introduced by compensatory movements and action modifications. Alternative methods need to be developed for efficient and objective assessment. In this study, we explore the potential of computer-based body tracking systems and classification tools to estimate the motor impairment of the more affected arm in stroke patients. Methods: We present a method for estimating clinical scores from movement parameters that are extracted from kinematic data recorded during unsupervised computer-based rehabilitation sessions. We identify a number of kinematic descriptors that characterise the patients' hemiparesis (e.g., movement smoothness, work area), we implement a double-noise model and perform a multivariate regression using clinical data from 98 stroke patients who completed a total of 191 sessions with RGS. Results: Our results reveal a new digital biomarker of arm function, the Total Goal-Directed Movement (TGDM), which relates to the patients work area during the execution of goal-oriented reaching movements. The model's performance to estimate FM-UE scores reaches an accuracy of R-2: 0.38 with an error (sigma: 12.8). Next, we evaluate its reliability (r = 0.89 for test-retest), longitudinal external validity (95% true positive rate), sensitivity, and generalisation to other tasks that involve planar reaching movements (R-2: 0.39). The model achieves comparable accuracy also for the Chedoke Arm and Hand Activity Inventory (R-2: 0.40) and Barthel Index (R-2: 0.35). Conclusions: Our results highlight the clinical value of kinematic data collected during unsupervised goal-oriented motor training with the RGS combined with data science techniques, and provide new insight into factors underlying recovery and its biomarkers

Role of the IL33 and IL1RL1 pathway in the pathogenesis of Immunoglobulin A vasculitis

Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that the IL33-IL1RL1 signalling pathway does not contribute to the genetic network underlying IgAV.Acknowledgements: We are indebted to the patients and healthy controls for their essential collaboration to this study. We also thank the National DNA Bank Repository (Salamanca) for supplying part of the control samples. This study was supported by European Union FEDER funds and `Fondo de Investigaciones Sanitarias´ (Grant PI18/00042) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). DP-P is a recipient of a Río Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) (Grant Number CM20/00006). SR-M is supported by funds of the RETICS Program (RD16/0012/0009) (ISCIII, cofunded by the European Regional Development Fund (ERDF)). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). BA-M is a recipient of a `López Albo´ Post-Residency Programme funded by Servicio Cántabro de Salud. LL-G is supported by funds from IDIVAL (INNVAL20/06). OG is staff personnel of Xunta de Galicia (Servizo Galego de Saude (SERGAS)) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and the European Union FEDER fund (Grant Numbers RD16/0012/0014 (RIER) and PI17/00409). He is beneficiary of project funds from the Research Executive Agency (REA) of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, project 734899—Olive-Net. RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by ESF (`Investing in your future´) (Grant Number CP16/00033)

VR-based rehabilitation strategies for functional motor recovery after stroke: individualization, reinforcement, and transfer

Stroke represents one of the main causes of adult disability and will be one of the main contributors to the burden of disease in 2030. However, our healthcare systems do not have enough resources to cover the current demand let alone its future increase. Partial and unmet rehabilitation needs may ultimately lead to a loss of functional independence. Hence, it is essential that new approaches are deployed that help to manage these chronic conditions and augment current rehabilitation approaches in order to enhance their e ciency. One of the latest approaches in the rehabilitation of a wide range of de- cits of the nervous system is based on the use of virtual reality (VR), which combines training scenarios with dedicated interface devices. It must be emphasized, however, that so far little work exists on the quantitative assessment of the clinical impact of VR based approaches. In this dissertation we present a number of studies that investigate the potential of VR technologies for motor recovery after stroke. First, we explore the transfer of VR-based rehabilitation systems from clinic based training to at home applications, and we compare the e ects of di erent rehabilitation approaches. Our results reveal that the development of compensatory behaviors, such as learned non-use, can greatly interfere with the recovery dynamics and prevent the retention of motor improvements. vii viii abstract Grounded in our observations, we introduce a novel rehabilitation strategy based on the sensorimotor augmentation of goal-oriented movements, that aims to correct these compensatory behaviors. We establish the principles behind this intervention using a computational model of recovery, and we validate its e cacy though a set of behavioral experiments that combine observational studies and a randomized controlled trial. This thesis work advances our understanding of the key mechanisms in uencing motor recovery after stroke, and provides a new perspective on how to maximize the retention of functional improvements.L'ictus representa una de les principals causes de discapacitat en els adults i serà un dels principals contribuents a la càrrega de la malaltia en 2030. No obstant això, els nostres sistemes de salut no compten amb els recursos suficients per cobrir la demanda actual i molt menys el seu futur creixement. Requeriments de rehabilitació parcial i necessitats d'aprenentatge no satisfetes poden, en última instància, conduir a una pèrdua d'independència funcional. Per tant, és essencial desplegar nous enfocaments que ajuden a tractar aquestes condicions cròniques i augmentar els enfocaments actuals de rehabilitació per tal de millorar la seva eficiència. Un dels últims enfocaments en la rehabilitació d'una àmplia gamma dels dèficits del sistema nerviós es basa en l'ús de la realitat virtual (VR), que combina escenaris d'entrenament amb dispositius d'interfície dedicats. Cal destacar, però, que existeix fins al moment poc treball en l'avaluació quantitativa de l'impacte clínic de la realitat virtual. En aquesta tesi es presenta un seguit d'estudis que investiguen el potencial de les tecnologies de realitat virtual per a la recuperació motora després de l'ictus. En primer lloc, s'explora la transferència de sistemes de rehabilitació basats en realitat virtual a l'àmbit domèstic, i es comparen els efectes de diferents enfocaments de rehabilitació. Els nostres resultats revelen que el desenvolupament de comportaments compensatoris, com ara la falta d'ús de les extremitats afectades, pot interferir en gran mesura amb la dinàmica de recuperació del pacient i prevenir la retenció de millores. En base a les nostres observacions, s'introdueix una estratègia de rehabilitació innovadora, basada en l'augment d'informació sensorial i motora dels moviments orientats a objectius, que té com a finalitat corregir aquestes conductes compensatòries. Establim els principis que fonamenten aquesta intervenció mitjançant un model computacional de recuperació, i validem la seva eficàcia a través d'una sèrie d'experiments comportamentals que combinen estudis observacionals i un assaig controlat aleatori amb pacients d'icus. Aquest treball de tesi avançaa el nostre coneixement sobre els mecanismes clau que influeixen en la recuperació motora després de l'accident cerebrovascular, i ofereix una nova perspectiva sobre com maximitzar la retenció de millores funcionals

VR-based rehabilitation strategies for functional motor recovery after stroke: individualization, reinforcement, and transfer

Stroke represents one of the main causes of adult disability and will be one of the main contributors to the burden of disease in 2030. However, our healthcare systems do not have enough resources to cover the current demand let alone its future increase. Partial and unmet rehabilitation needs may ultimately lead to a loss of functional independence. Hence, it is essential that new approaches are deployed that help to manage these chronic conditions and augment current rehabilitation approaches in order to enhance their e ciency. One of the latest approaches in the rehabilitation of a wide range of de- cits of the nervous system is based on the use of virtual reality (VR), which combines training scenarios with dedicated interface devices. It must be emphasized, however, that so far little work exists on the quantitative assessment of the clinical impact of VR based approaches. In this dissertation we present a number of studies that investigate the potential of VR technologies for motor recovery after stroke. First, we explore the transfer of VR-based rehabilitation systems from clinic based training to at home applications, and we compare the e ects of di erent rehabilitation approaches. Our results reveal that the development of compensatory behaviors, such as learned non-use, can greatly interfere with the recovery dynamics and prevent the retention of motor improvements. vii viii abstract Grounded in our observations, we introduce a novel rehabilitation strategy based on the sensorimotor augmentation of goal-oriented movements, that aims to correct these compensatory behaviors. We establish the principles behind this intervention using a computational model of recovery, and we validate its e cacy though a set of behavioral experiments that combine observational studies and a randomized controlled trial. This thesis work advances our understanding of the key mechanisms in uencing motor recovery after stroke, and provides a new perspective on how to maximize the retention of functional improvements.L'ictus representa una de les principals causes de discapacitat en els adults i serà un dels principals contribuents a la càrrega de la malaltia en 2030. No obstant això, els nostres sistemes de salut no compten amb els recursos suficients per cobrir la demanda actual i molt menys el seu futur creixement. Requeriments de rehabilitació parcial i necessitats d'aprenentatge no satisfetes poden, en última instància, conduir a una pèrdua d'independència funcional. Per tant, és essencial desplegar nous enfocaments que ajuden a tractar aquestes condicions cròniques i augmentar els enfocaments actuals de rehabilitació per tal de millorar la seva eficiència. Un dels últims enfocaments en la rehabilitació d'una àmplia gamma dels dèficits del sistema nerviós es basa en l'ús de la realitat virtual (VR), que combina escenaris d'entrenament amb dispositius d'interfície dedicats. Cal destacar, però, que existeix fins al moment poc treball en l'avaluació quantitativa de l'impacte clínic de la realitat virtual. En aquesta tesi es presenta un seguit d'estudis que investiguen el potencial de les tecnologies de realitat virtual per a la recuperació motora després de l'ictus. En primer lloc, s'explora la transferència de sistemes de rehabilitació basats en realitat virtual a l'àmbit domèstic, i es comparen els efectes de diferents enfocaments de rehabilitació. Els nostres resultats revelen que el desenvolupament de comportaments compensatoris, com ara la falta d'ús de les extremitats afectades, pot interferir en gran mesura amb la dinàmica de recuperació del pacient i prevenir la retenció de millores. En base a les nostres observacions, s'introdueix una estratègia de rehabilitació innovadora, basada en l'augment d'informació sensorial i motora dels moviments orientats a objectius, que té com a finalitat corregir aquestes conductes compensatòries. Establim els principis que fonamenten aquesta intervenció mitjançant un model computacional de recuperació, i validem la seva eficàcia a través d'una sèrie d'experiments comportamentals que combinen estudis observacionals i un assaig controlat aleatori amb pacients d'icus. Aquest treball de tesi avançaa el nostre coneixement sobre els mecanismes clau que influeixen en la recuperació motora després de l'accident cerebrovascular, i ofereix una nova perspectiva sobre com maximitzar la retenció de millores funcionals

Challenging the Boundaries of the Physical Self: Distal Cues Impact Body Ownership

The unique ability to identify one's own body and experience it as one's own is fundamental in goal-oriented behavior and survival. However, the mechanisms underlying the so-called body ownership are yet not fully understood. Evidence based on Rubber Hand Illusion (RHI) paradigms has demonstrated that body ownership is a product of reception and integration of self and externally generated multisensory information, feedforward and feedback processing of sensorimotor signals, and prior knowledge about the body. Crucially, however, these designs commonly involve the processing of proximal modalities while the contribution of distal sensory signals to the experience of ownership remains elusive. Here we propose that, like any robust percept, body ownership depends on the integration and prediction across all sensory modalities, including distal sensory signals pertaining to the environment. To test our hypothesis, we created an embodied goal-oriented Virtual Air Hockey Task, in which participants were to hit a virtual puck into a goal. In two conditions, we manipulated the congruency of distal multisensory cues (auditory and visual) while preserving proximal and action-driven signals entirely predictable. Compared to a fully congruent condition, our results revealed a significant decrease on three dimensions of ownership evaluation when distal signals were incongruent, including the subjective report as well as physiological and kinematic responses to an unexpected threat. Together, these findings support the notion that the way we represent our body is contingent upon all the sensory stimuli, including distal and action-independent signals. The present data extend the current framework of body ownership and may also find applications in rehabilitation scenarios.</p

Effect of specific over nonspecific VR-based rehabilitation on poststroke motor recovery: A systematic meta-analysis

Background. Despite the rise of virtual reality (VR)-based interventions in stroke rehabilitation over the past decade, no consensus has been reached on its efficacy. This ostensibly puzzling outcome might not be that surprising given that VR is intrinsically neutral to its use—that is, an intervention is effective because of its ability to mobilize recovery mechanisms, not its technology. As VR systems specifically built for rehabilitation might capitalize better on the advantages of technology to implement neuroscientifically grounded protocols, they might be more effective than those designed for recreational gaming. Objective. We evaluate the efficacy of specific VR (SVR) and nonspecific VR (NSVR) systems for rehabilitating upper-limb function and activity after stroke. Methods. We conducted a systematic search for randomized controlled trials with adult stroke patients to analyze the effect of SVR or NSVR systems versus conventional therapy (CT). Results. We identified 30 studies including 1473 patients. SVR showed a significant impact on body function (standardized mean difference [SMD] = 0.23; 95% CI = 0.10 to 0.36; P = .0007) versus CT, whereas NSVR did not (SMD = 0.16; 95% CI = −0.14 to 0.47; P = .30). This result was replicated in activity measures. Conclusions. Our results suggest that SVR systems are more beneficial than CT for upper-limb recovery, whereas NSVR systems are not. Additionally, we identified 6 principles of neurorehabilitation that are shared across SVR systems and are possibly responsible for their positive effect. These findings may disambiguate the contradictory results found in the current literature