Multiscale effects of excitatory-inhibitory homeostasis in lesioned cortical networks: A computational study.

Stroke-related disruptions in functional connectivity (FC) often spread beyond lesioned areas and, given the localized nature of lesions, it is unclear how the recovery of FC is orchestrated on a global scale. Since recovery is accompanied by long-term changes in excitability, we propose excitatory-inhibitory (E-I) homeostasis as a driving mechanism. We present a large-scale model of the neocortex, with synaptic scaling of local inhibition, showing how E-I homeostasis can drive the post-lesion restoration of FC and linking it to changes in excitability. We show that functional networks could reorganize to recover disrupted modularity and small-worldness, but not network dynamics, suggesting the need to consider forms of plasticity beyond synaptic scaling of inhibition. On average, we observed widespread increases in excitability, with the emergence of complex lesion-dependent patterns related to biomarkers of relevant side effects of stroke, such as epilepsy, depression and chronic pain. In summary, our results show that the effects of E-I homeostasis extend beyond local E-I balance, driving the restoration of global properties of FC, and relating to post-stroke symptomatology. Therefore, we suggest the framework of E-I homeostasis as a relevant theoretical foundation for the study of stroke recovery and for understanding the emergence of meaningful features of FC from local dynamics.

Volitional learning promotes theta phase coding in the human hippocampus.

Electrophysiological studies in rodents show that active navigation enhances hippocampal theta oscillations (4-12 Hz), providing a temporal framework for stimulus-related neural codes. Here we show that active learning promotes a similar phase coding regime in humans, although in a lower frequency range (3-8 Hz). We analyzed intracranial electroencephalography (iEEG) from epilepsy patients who studied images under either volitional or passive learning conditions. Active learning increased memory performance and hippocampal theta oscillations and promoted a more accurate reactivation of stimulus-specific information during memory retrieval. Representational signals were clustered to opposite phases of the theta cycle during encoding and retrieval. Critically, during active but not passive learning, the temporal structure of intracycle reactivations in theta reflected the semantic similarity of stimuli, segregating conceptually similar items into more distant theta phases. Taken together, these results demonstrate a multilayered mechanism by which active learning improves memory via a phylogenetically old phase coding scheme.

Multi-modal and multi-model interrogation of large-scale functional brain networks.

Existing whole-brain models are generally tailored to the modelling of a particular data modality (e.g., fMRI or MEG/EEG). We propose that despite the differing aspects of neural activity each modality captures, they originate from shared network dynamics. Building on the universal principles of self-organising delay-coupled nonlinear systems, we aim to link distinct features of brain activity - captured across modalities - to the dynamics unfolding on a macroscopic structural connectome. To jointly predict connectivity, spatiotemporal and transient features of distinct signal modalities, we consider two large-scale models - the Stuart Landau and Wilson and Cowan models - which generate short-lived 40 Hz oscillations with varying levels of realism. To this end, we measure features of functional connectivity and metastable oscillatory modes (MOMs) in fMRI and MEG signals - and compare them against simulated data. We show that both models can represent MEG functional connectivity (FC), functional connectivity dynamics (FCD) and generate MOMs to a comparable degree. This is achieved by adjusting the global coupling and mean conduction time delay and, in the WC model, through the inclusion of balance between excitation and inhibition. For both models, the omission of delays dramatically decreased the performance. For fMRI, the SL model performed worse for FCD and MOMs, highlighting the importance of balanced dynamics for the emergence of spatiotemporal and transient patterns of ultra-slow dynamics. Notably, optimal working points varied across modalities and no model was able to achieve a correlation with empirical FC higher than 0.4 across modalities for the same set of parameters. Nonetheless, both displayed the emergence of FC patterns that extended beyond the constraints of the anatomical structure. Finally, we show that both models can generate MOMs with empirical-like properties such as size (number of brain regions engaging in a mode) and duration (continuous time interval during which a mode appears). Our results demonstrate the emergence of static and dynamic properties of neural activity at different timescales from networks of delay-coupled oscillators at 40 Hz. Given the higher dependence of simulated FC on the underlying structural connectivity, we suggest that mesoscale heterogeneities in neural circuitry may be critical for the emergence of parallel cross-modal functional networks and should be accounted for in future modelling endeavours.

Saccade rate is associated with recall of items in working memory.

Working memory has been shown to rely on theta oscillations' phase synchronicity for item encoding and recall. At the same time, saccadic eye movements during visual exploration have been observed to trigger theta-phase resets, raising the question of whether the neuronal substrates of mnemonic processing rely on motor-evoked responses. To quantify the relationship between saccades and working memory load, we recorded eye tracking and behavioral data from human participants simultaneously performing an n-back Sternberg auditory task and a hue-based catch detection task. In addition to task-specific interference in performance, we also found that saccade rate was modulated by working memory load in the Sternberg task's preresponse stage. Our results support the possibility of interplay between saccades and hippocampal theta during working memory retrieval of items.

Rehabilitation Gaming System for Alcohol-Related Cognitive Impairment: A Pilot Usability Study.

AIMS: Cognitive impairment in patients with alcohol use disorder (AUD) is highly prevalent, and it negatively impacts treatment outcome. However, this condition is neither systematically assessed nor treated. Thus, we aimed to explore the usability of a virtual reality-based protocol ('Rehabilitation Gaming System', RGS) for patients with AUD. METHODS: Twenty AUD patients (50% also cognitive impairment) underwent a single session of the RGS protocol (four cognitive training tasks, 10 minutes each). System Usability Scale (SUS) and Post-Study System Usability Questionnaire (PSSUQ) were applied to assess the RGS usability and patients' satisfaction with it. Also, the Perceived Competence Scale was administered to assess the patients' feelings of competence when using the training protocol. Comparisons of the responses to these questionnaires were performed between AUD patients with cognitive impairment and those without cognitive impairment. RESULTS: RGS usability was very positively rated (median SUS score = 80, Interquartile Range, IQR = 68.13-86-88). No significant differences were found in the median SUS scores for any of the sociodemographic or clinical variables, excepting for gender (women median score = 85; IQR = 80-94.38 vs. men median score = 71.25; IQR = 61.25-89.25; P-value = 0.035). The quality of the information provided by the RGS training scenarios and the usability were positively rated (PSSUQ), and patients experienced high feelings of competence. CONCLUSIONS: The RGS has been found to be usable in the short term and patients with AUD stated to be satisfied with it. Future larger, randomized trials are needed to explore the effectiveness of this tool to help overcome the cognitive deficits in AUD patients.

Escaping from the IIT Munchausen method: Re-establishing the scientific method in the study of consciousness.

Integrated information theory (IIT) is an example of "ironic science" and obstructs the scientific study of consciousness. By confusing the ontological status of a method to quantify network complexity with that of a theory of consciousness, IIT has to square the circle and spirals toward its panpsychism conclusion. I analyze the consequences of this fallacy and suggest how the study of consciousness can be brought back into the realm of rational, empirical science.

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.

Multisensory cueing facilitates naming in aphasia.

BACKGROUND: Impaired naming is a ubiquitous symptom in all types of aphasia, which often adversely impacts independence, quality of life, and recovery of affected individuals. Previous research has demonstrated that naming can be facilitated by phonological and semantic cueing strategies that are largely incorporated into the treatment of anomic disturbances. Beneficial effects of cueing, whereby naming becomes faster and more accurate, are often attributed to the priming mechanisms occurring within the distributed language network. OBJECTIVE: We proposed and explored two novel cueing techniques: (1) Silent Visuomotor Cues (SVC), which provided articulatory information of target words presented in the form of silent videos, and (2) Semantic Auditory Cues (SAC), which consisted of acoustic information semantically relevant to target words (ringing for "telephone"). Grounded in neurophysiological evidence, we hypothesized that both SVC and SAC might aid communicative effectiveness possibly by triggering activity in perceptual and semantic language regions, respectively. METHODS: Ten participants with chronic non-fluent aphasia were recruited for a longitudinal clinical intervention. Participants were split into dyads (i.e., five pairs of two participants) and required to engage in a turn-based peer-to-peer language game using the Rehabilitation Gaming System for aphasia (RGSa). The objective of the RGSa sessions was to practice communicative acts, such as making a request. We administered SVCs and SACs in a pseudorandomized manner at the moment when the active player selected the object to be requested from the interlocutor. For the analysis, we compared the times from selection to the reception of the desired object between cued and non-cued trials. RESULTS: Naming accuracy, as measured by a standard clinical scale, significantly improved for all stimuli at each evaluation point, including the follow-up. Moreover, the results yielded beneficial effects of both SVC and SAC cues on word naming, especially at the early intervention sessions when the exposure to the target lexicon was infrequent. CONCLUSIONS: This study supports the efficacy of the proposed cueing strategies which could be integrated into the clinic or mobile technology to aid naming even at the chronic stages of aphasia. These findings are consistent with sensorimotor accounts of language processing, suggesting a coupling between language, motor, and semantic brain regions. TRIAL REGISTRATION: NCT02928822 . Registered 30 May 2016.

Augmented Dyadic Therapy Boosts Recovery of Language Function in Patients With Nonfluent Aphasia.

Background and Purpose- Evidence suggests that therapy can be effective in recovering from aphasia, provided that it consists of socially embedded, intensive training of behaviorally relevant tasks. However, the resources of healthcare systems are often too limited to provide such treatment at sufficient dosage. Hence, there is a need for evidence-based, cost-effective rehabilitation methods. Here, we asked whether virtual reality-based treatment grounded in the principles of use-dependent learning, behavioral relevance, and intensity positively impacts recovery from nonfluent aphasia. Methods- Seventeen patients with chronic nonfluent aphasia underwent intensive therapy in a randomized, controlled, parallel-group trial. Participants were assigned to the control group (N=8) receiving standard treatment or to the experimental group (N=9) receiving augmented embodied therapy with the Rehabilitation Gaming System for aphasia. All Rehabilitation Gaming System for aphasia sessions were supervised by an assistant who monitored the patients but did not offer any elements of standard therapy. Both interventions were matched for intensity and materials. Results- Our results revealed that at the end of the treatment both groups significantly improved on the primary outcome measure (Boston Diagnostic Aphasia Examination: control group, P=0.04; experimental group, P=0.01), and the secondary outcome measure (lexical access-vocabulary test: control group, P=0.01; experimental group, P=0.007). However, only the Rehabilitation Gaming System for aphasia group improved on the Communicative Aphasia Log ( P=0.01). The follow-up assessment (week 16) demonstrated that while both groups retained vocabulary-related changes (control group, P=0.01; experimental group, P=0.007), only the Rehabilitation Gaming System for aphasia group showed therapy-induced improvements in language ( P=0.01) and communication ( P=0.05). Conclusions- Our results demonstrate the effectiveness of Rehabilitation Gaming System for aphasia for improving language and communication in patients with chronic aphasia suggesting that current challenges faced by the healthcare system in the treatment of stroke might be effectively addressed by augmenting traditional therapy with computer-based methods. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02928822.

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.

A computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice.

Bacterial lipopolysaccharide (LPS) induces an acute inflammatory response across multiple organs, primarily via Toll-like receptor 4 (TLR4). We sought to define novel aspects of the complex spatiotemporal dynamics of LPS-induced inflammation using computational modeling, with a special focus on the timing of pathological systemic spillover. An analysis of principal drivers of LPS-induced inflammation in the heart, gut, lung, liver, spleen, and kidney to assess organ-specific dynamics, as well as in the plasma (as an assessment of systemic spillover), was carried out using data on 20 protein-level inflammatory mediators measured over 0-48h in both C57BL/6 and TLR4-null mice. Using a suite of computational techniques, including a time-interval variant of Principal Component Analysis, we confirm key roles for cytokines such as tumor necrosis factor-α and interleukin-17A, define a temporal hierarchy of organ-localized inflammation, and infer the point at which organ-localized inflammation spills over systemically. Thus, by employing a systems biology approach, we obtain a novel perspective on the time- and organ-specific components in the propagation of acute systemic inflammation.

Cerebellar alterations in cannabis users: A systematic review.

Cannabis is the most used illicit substance in the world. As many countries are moving towards decriminalization, it is crucial to determine whether and how cannabis use affects human brain and behavior. The role of the cerebellum in cognition, emotion, learning, and addiction is increasingly recognized. Because of its high density in CB1 receptors, it is expected to be highly affected by cannabis use. The aim of this systematic review is to investigate how cannabis use affects cerebellar structure and function, as well as cerebellar-dependent behavioral tasks. Three databases were searched for peer-reviewed literature published until March 2018. We included studies that focused on cannabis effects on cerebellar structure, function, or cerebellar-dependent behavioral tasks. A total of 348 unique records were screened, and 40 studies were included in the qualitative synthesis. The most consistent findings include (1) increases in cerebellar gray matter volume after chronic cannabis use, (2) alteration of cerebellar resting state activity after acute or chronic use, and (3) deficits in memory, decision making, and associative learning. Age of onset and higher exposure to cannabis use were frequently associated with increased cannabis-induced alterations. Chronic cannabis use is associated with alterations in cerebellar structure and function, as well as with deficits in behavioral paradigms that involve the cerebellum (eg, eyeblink conditioning, memory, and decision making). Future studies should consider tobacco as confounding factor and use standardized methods for assessing cannabis use. Paradigms exploring the functional activity of the cerebellum may prove useful as monitoring tools of cannabis-induced impairment.

Beyond Neural Coding? Lessons from Perceptual Control Theory.

Pointing to similarities between challenges encountered in today's neural coding and twentieth-century behaviorism, we draw attention to lessons learned from resolving the latter. In particular, Perceptual Control Theory posits behavior as a closed-loop control process with immediate and teleological causes. With two examples, we illustrate how these ideas may also address challenges facing current neural coding paradigms.

Long-term spatial clustering in free recall.

We explored the influence of space on the organisation of items in long-term memory. In two experiments, we asked our participants to explore a virtual environment and memorise discrete items presented at specific locations. Memory for those items was later on tested in immediate (T1) and 24 hours delayed (T2) free recall tests, in which subjects were asked to recall as many items as possible in any order. In experiment 2, we further examined the contribution of active and passive navigation in recollection dynamics. Results across experiments revealed a significant tendency for participants to consecutively recall items that were encountered in proximate locations during learning. Moreover, the degree of spatial organisation and the total number of items recalled were positively correlated in the immediate and the delayed tests. Results from experiment 2 indicated that the spatial clustering of items was independent of navigation types. Our results highlight the long-term stability of spatial clustering effects and their correlation with recall performance, complementing previous results collected in immediate or briefly delayed tests.

The perceptual shaping of anticipatory actions.

Humans display anticipatory motor responses to minimize the adverse effects of predictable perturbations. A widely accepted explanation for this behaviour relies on the notion of an inverse model that, learning from motor errors, anticipates corrective responses. Here, we propose and validate the alternative hypothesis that anticipatory control can be realized through a cascade of purely sensory predictions that drive the motor system, reflecting the causal sequence of the perceptual events preceding the error. We compare both hypotheses in a simulated anticipatory postural adjustment task. We observe that adaptation in the sensory domain, but not in the motor one, supports the robust and generalizable anticipatory control characteristic of biological systems. Our proposal unites the neurobiology of the cerebellum with the theory of active inference and provides a concrete implementation of its core tenets with great relevance both to our understanding of biological control systems and, possibly, to their emulation in complex artefacts.

Consensus Paper: Towards a Systems-Level View of Cerebellar Function: the Interplay Between Cerebellum, Basal Ganglia, and Cortex.

Despite increasing evidence suggesting the cerebellum works in concert with the cortex and basal ganglia, the nature of the reciprocal interactions between these three brain regions remains unclear. This consensus paper gathers diverse recent views on a variety of important roles played by the cerebellum within the cerebello-basal ganglia-thalamo-cortical system across a range of motor and cognitive functions. The paper includes theoretical and empirical contributions, which cover the following topics: recent evidence supporting the dynamical interplay between cerebellum, basal ganglia, and cortical areas in humans and other animals; theoretical neuroscience perspectives and empirical evidence on the reciprocal influences between cerebellum, basal ganglia, and cortex in learning and control processes; and data suggesting possible roles of the cerebellum in basal ganglia movement disorders. Although starting from different backgrounds and dealing with different topics, all the contributors agree that viewing the cerebellum, basal ganglia, and cortex as an integrated system enables us to understand the function of these areas in radically different ways. In addition, there is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions. The paper reports the most advanced perspectives on the role of the cerebellum within the cerebello-basal ganglia-thalamo-cortical system and illustrates other elements of consensus as well as disagreements and open questions in the field.

The Impact of Cortical Lesions on Thalamo-Cortical Network Dynamics after Acute Ischaemic Stroke: A Combined Experimental and Theoretical Study.

The neocortex and thalamus provide a core substrate for perception, cognition, and action, and are interconnected through different direct and indirect pathways that maintain specific dynamics associated with functional states including wakefulness and sleep. It has been shown that a lack of excitation, or enhanced subcortical inhibition, can disrupt this system and drive thalamic nuclei into an attractor state of low-frequency bursting and further entrainment of thalamo-cortical circuits, also called thalamo-cortical dysrhythmia (TCD). The question remains however whether similar TCD-like phenomena can arise with a cortical origin. For instance, in stroke, a cortical lesion could disrupt thalamo-cortical interactions through an attenuation of the excitatory drive onto the thalamus, creating an imbalance between excitation and inhibition that can lead to a state of TCD. Here we tested this hypothesis by comparing the resting-state EEG recordings of acute ischaemic stroke patients (N = 21) with those of healthy, age-matched control-subjects (N = 17). We observed that these patients displayed the hallmarks of TCD: a characteristic downward shift of dominant α-peaks in the EEG power spectra, together with increased power over the lower frequencies (δ and θ-range). Contrary to general observations in TCD, the patients also displayed a broad reduction in ß-band activity. In order to explain the genesis of this stroke-induced TCD, we developed a biologically constrained model of a general thalamo-cortical module, allowing us to identify the specific cellular and network mechanisms involved. Our model showed that a lesion in the cortical component leads to sustained cell membrane hyperpolarization in the corresponding thalamic relay neurons, that in turn leads to the de-inactivation of voltage-gated T-type Ca2+-channels, switching neurons from tonic spiking to a pathological bursting regime. This thalamic bursting synchronises activity on a population level through divergent intrathalamic circuits, and entrains thalamo-cortical pathways by means of propagating low-frequency oscillations beyond the restricted region of the lesion. Hence, pathological stroke-induced thalamo-cortical dynamics can be the source of diaschisis, and account for the dissociation between lesion location and non-specific symptoms of stroke such as neuropathic pain and hemispatial neglect.

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 .