Chronic cannabis use affects cerebellum dependent visuomotor adaptation.

BACKGROUND: Cannabis is one of the most commonly used substances in the world. However, its effects on human cognition are not yet fully understood. Although the cerebellum has the highest density of cannabinoid receptor type 1 (CB1R) in the human brain, literature on how cannabis use affects cerebellar-dependent learning is sparse. This study examined the effect of chronic cannabis use on sensorimotor adaptation, a cerebellar-mediated task, which has been suggested to depend on endocannabinoid signaling. METHODS: Chronic cannabis users (n = 27) with no psychiatric comorbidities and healthy, cannabis-naïve controls (n = 25) were evaluated using a visuomotor rotation task. Cannabis users were re-tested after 1 month of abstinence (n = 13) to assess whether initial differences in performance would persist after cessation of use. RESULTS: Cannabis users showed lower adaptation rates compared to controls at the first time point. However, this difference in performance did not persist when participants were retested after one month of abstinence (n = 13). Healthy controls showed attenuated implicit learning in the late phase of the adaptation during re-exposure, which was not present in cannabis users. This explains the lack of between group differences in the second time point and suggests a potential alteration of synaptic plasticity required for cerebellar learning in cannabis users. CONCLUSIONS: Overall, our results suggest that chronic cannabis users show alterations in sensorimotor adaptation, likely due to a saturation of the endocannabinoid system after chronic cannabis use.

Bringing rehabilitation home with an e-health platform to treat stroke patients: study protocol of a randomized clinical trial (RGS@home).

BACKGROUND: There is a pressing need for scalable healthcare solutions and a shift in the rehabilitation paradigm from hospitals to homes to tackle the increase in stroke incidence while reducing the practical and economic burden for patients, hospitals, and society. Digital health technologies can contribute to addressing this challenge; however, little is known about their effectiveness in at-home settings. In response, we have designed the RGS@home study to investigate the effectiveness, acceptance, and cost of a deep tech solution called the Rehabilitation Gaming System (RGS). RGS is a cloud-based system for delivering AI-enhanced rehabilitation using virtual reality, motion capture, and wearables that can be used in the hospital and at home. The core principles of the brain theory-based RGS intervention are to deliver rehabilitation exercises in the form of embodied, goal-oriented, and task-specific action. METHODS: The RGS@home study is a randomized longitudinal clinical trial designed to assess whether the combination of the RGS intervention with standard care is superior to standard care alone for the functional recovery of stroke patients at the hospital and at home. The study is conducted in collaboration with hospitals in Spain, Sweden, and France and includes inpatients and outpatients at subacute and chronic stages post-stroke. The intervention duration is 3 months with assessment at baseline and after 3, 6, and 12 months. The impact of RGS is evaluated in terms of quality of life measurements, usability, and acceptance using standardized clinical scales, together with health economic analysis. So far, one-third of the patients expected to participate in the study have been recruited (N = 90, mean age 60, days after stroke ≥ 30 days). The trial will end in July 2023. DISCUSSION: We predict an improvement in the patients' recovery, high acceptance, and reduced costs due to a soft landing from the clinic to home rehabilitation. In addition, the data provided will allow us to assess whether the prescription of therapy at home can counteract deterioration and improve quality of life while also identifying new standards for online and remote assessment, diagnostics, and intervention across European hospitals. TRIAL REGISTRATION: C linicalTrials.gov NCT04620707. Registered on November 3, 2020.

Using the Barthel Index and modified Rankin Scale as Outcome Measures for Stroke Rehabilitation Trials; A Comparison of Minimum Sample Size Requirements.

OBJECTIVES: Underpowered trials risk inaccurate results. Recruitment to stroke rehabilitation randomised controlled trials (RCTs) is often a challenge. Statistical simulations offer an important opportunity to explore the adequacy of sample sizes in the context of specific outcome measures. We aimed to examine and compare the adequacy of stroke rehabilitation RCT sample sizes using the Barthel Index (BI) or modified Rankin Scale (mRS) as primary outcomes. METHODS: We conducted computer simulations using typical experimental event rates (EER) and control event rates (CER) based on individual participant data (IPD) from stroke rehabilitation RCTs. Event rates are the proportion of participants who experienced clinically relevant improvements in the RCT experimental and control groups. We examined minimum sample size requirements and estimated the number of participants required to achieve a number needed to treat within clinically acceptable boundaries for the BI and mRS. RESULTS: We secured 2350 IPD (18 RCTs). For a 90% chance of statistical accuracy on the BI a rehabilitation RCT would require 273 participants per randomised group. Accurate interpretation of effect sizes would require 1000s of participants per group. Simulations for the mRS were not possible as a clinically relevant improvement was not detected when using this outcome measure. CONCLUSIONS: Stroke rehabilitation RCTs with large sample sizes are required for accurate interpretation of effect sizes based on the BI. The mRS lacked sensitivity to detect change and thus may be unsuitable as a primary outcome in stroke rehabilitation trials.

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.

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 [Formula: see text]: 0.38 with an error ([Formula: see text]: 12.8). Next, we evaluate its reliability ([Formula: see text] for test-retest), longitudinal external validity ([Formula: see text] true positive rate), sensitivity, and generalisation to other tasks that involve planar reaching movements ([Formula: see text]: 0.39). The model achieves comparable accuracy also for the Chedoke Arm and Hand Activity Inventory ([Formula: see text]: 0.40) and Barthel Index ([Formula: see text]: 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.

Adaptive conjunctive cognitive training (ACCT) in virtual reality for chronic stroke patients: a randomized controlled pilot trial.

BACKGROUND: Current evidence for the effectiveness of post-stroke cognitive rehabilitation is weak, possibly due to two reasons. First, patients typically express cognitive deficits in several domains. Therapies focusing on specific cognitive deficits might not address their interrelated neurological nature. Second, co-occurring psychological problems are often neglected or not diagnosed, although post-stroke depression is common and related to cognitive deficits. This pilot trial aims to test a rehabilitation program in virtual reality that trains various cognitive domains in conjunction, by adapting to the patient's disability and while investigating the influence of comorbidities. METHODS: Thirty community-dwelling stroke patients at the chronic stage and suffering from cognitive impairment performed 30 min of daily training for 6 weeks. The experimental group followed, so called, adaptive conjunctive cognitive training (ACCT) using RGS, whereas the control group solved standard cognitive tasks at home for an equivalent amount of time. A comprehensive test battery covering executive function, spatial awareness, attention, and memory as well as independence, depression, and motor impairment was applied at baseline, at 6 weeks and 18-weeks follow-up. RESULTS: At baseline, 75% of our sample had an impairment in more than one cognitive domain. The experimental group showed improvements in attention ([Formula: see text] (2) = 9.57, p < .01), spatial awareness ([Formula: see text] (2) = 11.23, p < .01) and generalized cognitive functioning ([Formula: see text] (2) = 15.5, p < .001). No significant change was seen in the executive function and memory domain. For the control group, no significant change over time was found. Further, they worsened in their depression level after treatment (T = 45, r = .72, p < .01) but returned to baseline at follow-up. The experimental group displayed a lower level of depression than the control group after treatment (Ws = 81.5, z = - 2.76, r = - .60, p < .01) and (Ws = 92, z = - 2.03, r = - .44, p < .05). CONCLUSIONS: ACCT positively influences attention and spatial awareness, as well as depressive mood in chronic stroke patients. TRIAL REGISTRATION: The trial was registered prospectively at ClinicalTrials.gov (NCT02816008) on June 21, 2016.

A critical time window for recovery extends beyond one-year post-stroke.

The impact of rehabilitation on post-stroke motor recovery and its dependency on the patient's chronicity remain unclear. The field has widely accepted the notion of a proportional recovery rule with a "critical window for recovery" within the first 3-6 mo poststroke. This hypothesis justifies the general cessation of physical therapy at chronic stages. However, the limits of this critical window have, so far, been poorly defined. In this analysis, we address this question, and we further explore the temporal structure of motor recovery using individual patient data from a homogeneous sample of 219 individuals with mild to moderate upper-limb hemiparesis. We observed that improvement in body function and structure was possible even at late chronic stages. A bootstrapping analysis revealed a gradient of enhanced sensitivity to treatment that extended beyond 12 mo poststroke. Clinical guidelines for rehabilitation should be revised in the context of this temporal structure. NEW & NOTEWORTHY Previous studies in humans suggest that there is a 3- to 6-mo "critical window" of heightened neuroplasticity poststroke. We analyze the temporal structure of recovery in patients with hemiparesis and uncover a precise gradient of enhanced sensitivity to treatment that expands far beyond the limits of the so-called critical window. These findings highlight the need for providing therapy to patients at the chronic and late chronic stages.

Principles of Neurorehabilitation After Stroke Based on Motor Learning and Brain Plasticity Mechanisms.

What are the principles underlying effective neurorehabilitation? The aim of neurorehabilitation is to exploit interventions based on human and animal studies about learning and adaptation, as well as to show that the activation of experience-dependent neuronal plasticity augments functional recovery after stroke. Instead of teaching compensatory strategies that do not reduce impairment but allow the patient to return home as soon as possible, functional recovery might be more sustainable as it ensures a long-term reduction in impairment and an improvement in quality of life. At the same time, neurorehabilitation permits the scientific community to collect valuable data, which allows inferring about the principles of brain organization. Hence neuroscience sheds light on the mechanisms of learning new functions or relearning lost ones. However, current rehabilitation methods lack the exact operationalization of evidence gained from skill learning literature, leading to an urgent need to bridge motor learning theory and present clinical work in order to identify a set of ingredients and practical applications that could guide future interventions. This work aims to unify the neuroscientific literature relevant to the recovery process and rehabilitation practice in order to provide a synthesis of the principles that constitute an effective neurorehabilitation approach. Previous attempts to achieve this goal either focused on a subset of principles or did not link clinical application to the principles of motor learning and recovery. We identified 15 principles of motor learning based on existing literature: massed practice, spaced practice, dosage, task-specific practice, goal-oriented practice, variable practice, increasing difficulty, multisensory stimulation, rhythmic cueing, explicit feedback/knowledge of results, implicit feedback/knowledge of performance, modulate effector selection, action observation/embodied practice, motor imagery, and social interaction. We comment on trials that successfully implemented these principles and report evidence from experiments with healthy individuals as well as clinical work.

Domiciliary VR-Based Therapy for Functional Recovery and Cortical Reorganization: Randomized Controlled Trial in Participants at the Chronic Stage Post Stroke.

BACKGROUND: Most stroke survivors continue to experience motor impairments even after hospital discharge. Virtual reality-based techniques have shown potential for rehabilitative training of these motor impairments. Here we assess the impact of at-home VR-based motor training on functional motor recovery, corticospinal excitability and cortical reorganization. OBJECTIVE: The aim of this study was to identify the effects of home-based VR-based motor rehabilitation on (1) cortical reorganization, (2) corticospinal tract, and (3) functional recovery after stroke in comparison to home-based occupational therapy. METHODS: We conducted a parallel-group, controlled trial to compare the effectiveness of domiciliary VR-based therapy with occupational therapy in inducing motor recovery of the upper extremities. A total of 35 participants with chronic stroke underwent 3 weeks of home-based treatment. A group of subjects was trained using a VR-based system for motor rehabilitation, while the control group followed a conventional therapy. Motor function was evaluated at baseline, after the intervention, and at 12-weeks follow-up. In a subgroup of subjects, we used Navigated Brain Stimulation (NBS) procedures to measure the effect of the interventions on corticospinal excitability and cortical reorganization. RESULTS: Results from the system's recordings and clinical evaluation showed significantly greater functional recovery for the experimental group when compared with the control group (1.53, SD 2.4 in Chedoke Arm and Hand Activity Inventory). However, functional improvements did not reach clinical significance. After the therapy, physiological measures obtained from a subgroup of subjects revealed an increased corticospinal excitability for distal muscles driven by the pathological hemisphere, that is, abductor pollicis brevis. We also observed a displacement of the centroid of the cortical map for each tested muscle in the damaged hemisphere, which strongly correlated with improvements in clinical scales. CONCLUSIONS: These findings suggest that, in chronic stages, remote delivery of customized VR-based motor training promotes functional gains that are accompanied by neuroplastic changes. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number NCT02699398 (Archived by ClinicalTrials.gov at https://clinicaltrials.gov/ct2/show/NCT02699398?term=NCT02699398&rank=1).

Conjunctive rehabilitation of multiple cognitive domains for chronic stroke patients in virtual reality.

Classically, cognitive deficits have been studied and treated in isolation from each other. A stroke patient is classified as being memory impaired, having executive dysfunction or showing attentional deficits after which a dedicated rehabilitation therapy is given. Studies seldom looked at the relationship between these different cognitive domains and syndromes, although, there is evidence that they might share common neuronal substrates and do not occur in isolation. Here, we propose a novel rehabilitation method in virtual reality to treat cognitive deficits in conjunction and report the preliminary results of an ongoing randomized controlled clinical trial. The current results suggest that in a homogeneous patient group the cognitive deficits are correlated and that the individual impairment level can be optimally addressed through an adaptive training paradigm.

Counteracting learned non-use in chronic stroke patients with reinforcement-induced movement therapy.

BACKGROUND: After stroke, patients who suffer from hemiparesis tend to suppress the use of the affected extremity, a condition called learned non-use. Consequently, the lack of training may lead to the progressive deterioration of motor function. Although Constraint-Induced Movement Therapies (CIMT) have shown to be effective in treating this condition, the method presents several limitations, and the high intensity of its protocols severely compromises its adherence. We propose a novel rehabilitation approach called Reinforcement-Induced Movement Therapy (RIMT), which proposes to restore motor function through maximizing arm use. This is achieved by exposing the patient to amplified goal-oriented movements in VR that match the intended actions of the patient. We hypothesize that through this method we can increase the patients self-efficacy, reverse learned non-use, and induce long-term motor improvements. METHODS: We conducted a randomized, double-blind, longitudinal clinical study with 18 chronic stroke patients. Patients performed 30 minutes of daily VR-based training during six weeks. During training, the experimental group experienced goal-oriented movement amplification in VR. The control group followed the same training protocol but without movement amplification. Evaluators blinded to group designation performed clinical measurements at the beginning, at the end of the training and at 12-weeks follow-up. We used the Fugl-Meyer Assessment for the upper extremities (UE-FM) (Sanford et al., Phys Ther 73:447-454, 1993) as a primary outcome measurement of motor recovery. Secondary outcome measurements included the Chedoke Arm and Hand Activity Inventory (CAHAI-7) (Barreca et al., Arch Phys Med Rehabil 6:1616-1622, 2005) for measuring functional motor gains in the performance of Activities of Daily Living (ADLs), the Barthel Index (BI) for the evaluation of the patient's perceived independence (Collin et al., Int Disabil Stud 10:61-63, 1988), and the Hamilton scale (Knesevich et al., Br J Psychiatr J Mental Sci 131:49-52, 1977) for the identification of improvements in mood disorders that could be induced by the reinforcement-based intervention. In order to study and predict the effects of this intervention we implemented a computational model of recovery after stroke. RESULTS: While both groups showed significant motor gains at 6-weeks post-treatment, only the experimental group continued to exhibit further gains in UE-FM at 12-weeks follow-up (p<.05). This improvement was accompanied by a significant increase in arm-use during training in the experimental group. CONCLUSIONS: Implicitly reinforcing arm-use by augmenting visuomotor feedback as proposed by RIMT seems beneficial for inducing significant improvement in chronic stroke patients. By challenging the patients' self-limiting believe system and perceived low self-efficacy this approach might counteract learned non-use. TRIAL REGISTRATION: Clinical Trials NCT02657070 .

The visual amplification of goal-oriented movements counteracts acquired non-use in hemiparetic stroke patients.

BACKGROUND: Stroke-induced impairments result from both primary and secondary causes, i.e. damage to the brain and the acquired non-use of the impaired limbs. Indeed, stroke patients often under-utilize their paretic limb despite sufficient residual motor function. We hypothesize that acquired non-use can be overcome by reinforcement-based training strategies. METHODS: Hemiparetic stroke patients (n = 20, 11 males, 9 right-sided hemiparesis) were asked to reach targets appearing in either the real world or in a virtual environment. Sessions were divided into 3 phases: baseline, intervention and washout. During the intervention the movement of the virtual representation of the patients' paretic limb was amplified towards the target. RESULTS: We found that the probability of using the paretic limb during washout was significantly higher in comparison to baseline. Patients showed generalization of these results by displaying a more substantial workspace in real world task. These gains correlated with changes in effector selection patterns. CONCLUSIONS: The amplification of the movement of the paretic limb in a virtual environment promotes the use of the paretic limb in stroke patients. Our findings indicate that reinforcement-based therapies may be an effective approach for counteracting learned non-use and may modulate motor performance in the real world.