Traditional versus progressive robot-assisted gait training in people with multiple sclerosis and severe gait disability: study protocol for the PROGR-EX randomised controlled trial.

Gait disorders are the most frequent symptoms associated to multiple sclerosis (MS). Robot-assisted gait training (RAGT) in people with MS (PwMS) has been proposed as a possible effective treatment option for severe motor disability without significant superiority when compared to intensive overground gait training (OGT). Furthermore, RAGT at high intensity may enhance fatigue and spasticity. This study aims to evaluate the effects of a low-intensity RAGT at progressively increasing intensity compared to conventional RAGT and OGT in PwMS and moderate to severe walking impairment. 24 PwMS will be recruited and assigned to one of the three treatment groups: low-intensity RAGT at progressively increasing intensity, conventional RAGT and OGT. All participants will receive 3-weekly treatment sessions of 3 hours each for 4 weeks. In the first 2 hours of treatment, all participants will receive a rehabilitation programme based on stretching exercises, muscle strengthening and educational interventions. During the last hour, subjects will undergo specific gait training according to the assignment group. Outcomes will be assessed before and after treatment and at 3-month follow-up. The primary outcome is walking speed. Secondary outcomes include mobility and balance, psychological measures, muscle oxygen consumption, electrical and haemodynamic brain activity, urinary biomarkers, usability, and acceptability of robotic devices for motor rehabilitation. The results of this study will provide a safe, affordable and non-operator-dependent, intervention for PwMS. Results in terms of functional, psychological, neurophysiological and biological outcomes will confirm our hypothesis. The study's trial registration number: NCT06381440.

The Effectiveness of Paired Associative Stimulation on Motor Recovery after Stroke: A Scoping Review.

Paired associative stimulation (PAS) is a non-invasive brain stimulation technique combining transcranial magnetic stimulation and peripheral nerve stimulation. PAS allows connections between cortical areas and peripheral nerves (C/P PAS) or between cortical regions (C/C PAS) to be strengthened or weakened by spike-timing-dependent neural plasticity mechanisms. Since PAS modulates both neurophysiological features and motor performance, there is growing interest in its application in neurorehabilitation. We aimed to synthesize evidence on the motor rehabilitation role of PAS in stroke patients. We performed a literature search following the PRISMA Extension for Scoping Reviews Framework. Eight studies were included: one investigated C/C PAS between the cerebellum and the affected primary motor area (M1), seven applied C/P PAS over the lesional, contralesional, or both M1. Seven studies evaluated the outcome on upper limb and one on lower limb motor recovery. Although several studies omit crucial methodological details, PAS highlighted effects mainly on corticospinal excitability, and, more rarely, an improvement in motor performance. However, most studies failed to prove a correlation between neurophysiological changes and motor improvement. Although current studies seem to suggest a role of PAS in post-stroke rehabilitation, their heterogeneity and limited number do not yet allow definitive conclusions to be drawn.

Blooming and pruning: learning from mistakes with memristive synapses.

Blooming and pruning is one of the most important developmental mechanisms of the biological brain in the first years of life, enabling it to adapt its network structure to the demands of the environment. The mechanism is thought to be fundamental for the development of cognitive skills. Inspired by this, Chialvo and Bak proposed in 1999 a learning scheme that learns from mistakes by eliminating from the initial surplus of synaptic connections those that lead to an undesirable outcome. Here, this idea is implemented in a neuromorphic circuit scheme using CMOS integrated HfO2-based memristive devices. The implemented two-layer neural network learns in a self-organized manner without positive reinforcement and exploits the inherent variability of the memristive devices. This approach provides hardware, local, and energy-efficient learning. A combined experimental and simulation-based parameter study is presented to find the relevant system and device parameters leading to a compact and robust memristive neuromorphic circuit that can handle association tasks.

Head-Mounted Displays for Upper Limb Stroke Rehabilitation: A Scoping Review.

Upper extremity (UE) paresis is one of the most frequent and disabling clinical consequences after stroke. Head-Mounted Displays (HMDs) are wearable virtual reality devices that seem effective in promoting the recovery of functional abilities by increasing adherence levels in this population. This scoping review is aimed at collecting available evidence on the use of HMD-based immersive virtual reality systems for UE rehabilitation treatment in stroke survivors. Four electronic bibliographic databases were consulted from inception until 18 January 2023. A total of 19 clinical trials in which HMDs were used as a clinical tool for increasing UE functioning, as a single intervention or in adjunct to other rehab treatments, were included; no restrictions were applied for UE paresis severity or stroke onset. The large majority of the clinical trials involved chronic stroke patients (15 out of 19), with a wide range of UE impairments. Overall, HMD use seemed to be well-tolerated and promising for increasing UE motor function in adult chronic stroke survivors, with benefits in subjects' arm use and independence. The possibility of executing highly realistic and task-oriented movements appears to be promising in enhancing gesture relevance, thus promoting new motor strategies in a "virtual ecological way". Across studies, we found a high heterogeneity in protocol design and a lack of reporting that prevents us drawing conclusions regarding potential subgroups of patients that could benefit more from HMD-based interventions or suggested treatment modalities.

Variations in Health-Related Quality of Life After Stroke: Insights From a Clinical Trial on Arm Rehabilitation With a Long-Term Follow-Up.

Despite rehabilitation, stroke patients continue to have impaired function and reduced health-related quality of life (HRQoL) even in a chronic stage. However, no clear information is available on long-term variations in HRQoL. In this study, we aimed to report the short- and long-term changes in HRQoL in a subacute stroke sample that was enrolled in a clinical trial on arm rehabilitation. Thirty-nine stroke survivors (62% male, mean age 68 years) were assessed using the Stroke Impact Scale Version 2.0 (SIS 2.0) pre and post rehabilitation and at 6 months and 6 years follow-up. Long-term changes in physical function were explored through clinically meaningful changes in the Stroke Impact Scale-16 (SIS-16). After rehabilitation (P < .001), an overall improvement was found in all SIS domains except the memory and thinking, emotions, and communication domains. The baseline SIS-16 score (P < .001), the presence of a sensory deficit, and rehabilitation setting (P < .05) were factors related to the SIS-16 domain scores at the end of rehabilitation and at 6 months follow-up. Patients showed the most deterioration in the mobility (P < .001), strength (P < .003), and hand function (P < .05) domains 6 years after stroke. Stroke severity, male gender, and age ⩾65 years are related with a long-term HRQoL reduction after stroke.

A Multimodal Analysis to Explore Upper Limb Motor Recovery at 4 Weeks After Stroke: Insights From EEG and Kinematics Measures.

Background. Stroke is a leading cause of death and disability worldwide and there is a very short period of increased synaptic plasticity, fundamental in motor recovery. Thus, it is crucial to acquire data to guide the rehabilitation treatment. Promising results have been achieved with kinematics and neurophysiological data, but currently, few studies integrate these different modalities. Objectives. We explored the correlations between standardized clinical scales, kinematic data, and EEG measures 4 weeks after stroke. Methods. 26 patients were considered. Among them, 20 patients also performed the EEG study, beyond the kinematic analysis, at 4 weeks. Results. We found correlations between the Fugl-Meyer Assessment-Upper Extremity, movement duration, smoothness measures, and velocity peaks. Moreover, EEG measures showed a tendency for the healthy hemisphere to vicariate the affected one in patients characterized by better clinical conditions. Conclusions. These results suggest the relevance of kinematic (in particular movement duration and smoothness) and EEG biomarkers to evaluate post-stroke recovery. We emphasize the importance of integrating clinical data with kinematic and EEG analyses from the early stroke stages, in order to guide rehabilitation strategies to best leverage the short period of increased synaptic plasticity.

Quantitative Comparison of Hand Kinematics Measured with a Markerless Commercial Head-Mounted Display and a Marker-Based Motion Capture System in Stroke Survivors.

Upper-limb paresis is common after stroke. An important tool to assess motor recovery is to use marker-based motion capture systems to measure the kinematic characteristics of patients' movements in ecological scenarios. These systems are, however, very expensive and not readily available for many rehabilitation units. Here, we explored whether the markerless hand motion capabilities of the cost-effective Oculus Quest head-mounted display could be used to provide clinically meaningful measures. A total of 14 stroke patients executed ecologically relevant upper-limb tasks in an immersive virtual environment. During task execution, we recorded their hand movements simultaneously by means of the Oculus Quest's and a marker-based motion capture system. Our results showed that the markerless estimates of the hand position and peak velocity provided by the Oculus Quest were in very close agreement with those provided by a marker-based commercial system with their regression line having a slope close to 1 (maximum distance: mean slope = 0.94 ± 0.1; peak velocity: mean slope = 1.06 ± 0.12). Furthermore, the Oculus Quest had virtually the same sensitivity as that of a commercial system in distinguishing healthy from pathological kinematic measures. The Oculus Quest was as accurate as a commercial marker-based system in measuring clinically meaningful upper-limb kinematic parameters in stroke patients.

Effects of Exercise, Rehabilitation, and Nutritional Approaches on Body Composition and Bone Density in People with Multiple Sclerosis: A Systematic Review and Meta-Analysis.

People with multiple sclerosis (pwMS) are affected by a wide range of disabilities, including a decrease in bone mineral density (BMD) and a worsening of body composition (BC), which negatively impact their quality of life quality. This study aims to analyze the effects of nonpharmacological interventions-in particular, physical activity, nutritional approaches, and rehabilitation-on BC and BMD in pwMS. This systematic review and meta-analysis was performed following the updated version of the PRISMA guidelines. In July 2022, five databases (MEDLINE, Embase, The Cochrane Library, Google Scholar, Web of Science) and gray literature were screened. Relevant articles published between 1 January 1990 and 1 September 2022 in any language were included. Outcomes of interest were anthropometric, BC measures, and BMD. The RoB 2.0 tool was used to assess the risk of bias. After duplicates elimination, 1120 records were screened, and 36 studies were included. A total of 25 articles were focused on physical activity and rehabilitation, 10 on nutrition, and 1 on multimodal intervention. One-third of the studies were judged to be at high risk of bias. The meta-analysis showed a high degree of heterogeneity due to the high variability in disease severity and intervention duration, intensity, frequency, and type. In general, no intervention showed consistent positive effects on BC. However, the most promising interventions seemed to be high-intensity training and ketogenic diets. Only a few studies considered BMD, and the results are inconsistent. Nevertheless, more studies are needed in order to confirm these results.

Physiotherapy management of nociplastic pain: A Delphi study of Italian specialists.

BACKGROUND AND PURPOSE: Nociplastic pain due to central sensitization (CS) is common in people suffering from chronic pain, but no clinical practice guideline is available in rehabilitative settings for patients' management. The aim of this study is to achieve expert consensus on physiotherapy competencies in the management of people with nociplastic pain and suspected CS mechanisms. METHODS: A web-based Delphi process was employed. Experts in the rehabilitation field were recruited following pre-defined eligibility criteria. Following completion of three Delphi rounds, the final list of competencies was generated. RESULTS: In all, 23 participants were recruited. They all completed Round 1 (23/23, 100%), twenty Round 2 and Round 3 (20/23, 87%). Following Round 1, seven areas were identified by the panel as crucial for CS physiotherapy management; 19 competencies out of 40 reached the consensus between experts, and nine additional competencies were added to Round 2 following literary review. Round 2 identified the agreement for all the 29 competencies. During Round 3, all the experts confirmed the final list generated through the consensus process. DISCUSSION: An agreement between experts was found for the final list of competencies that a physiotherapist should implement every time it approaches people with suspected CS mechanisms. Further research is needed to support the clinical utility of our findings and their applicability in daily practice.

Action Observation Therapy for Arm Recovery after Stroke: A Preliminary Investigation on a Novel Protocol with EEG Monitoring.

This preliminary study introduces a novel action observation therapy (AOT) protocol associated with electroencephalographic (EEG) monitoring to be used in the future as a rehabilitation strategy for the upper limb in patients with subacute stroke. To provide initial evidence on the usefulness of this method, we compared the outcome of 11 patients who received daily AOT for three weeks with that of patients who undertook two other approaches recently investigated by our group, namely intensive conventional therapy (ICT), and robot-assisted therapy combined with functional electrical stimulation (RAT-FES). The three rehabilitative interventions showed similar arm motor recovery as indexed by Fugl-Meyer's assessment of the upper extremity (FMA_UE) and box and block test (BBT). The improvement in the FMA_UE was yet more favourable in patients with mild/moderate motor impairments who received AOT, in contrast with patients carrying similar disabilities who received the other two treatments. This suggests that AOT might be more effective in this subgroup of patients, perhaps because the integrity of their mirror neurons system (MNS) was more preserved, as indexed by EEG recording from central electrodes during action observation. In conclusion, AOT may reveal an effective rehabilitative tool in patients with subacute stroke; the EEG evaluation of MNS integrity may help to select patients who could maximally benefit from this intervention.

Anti-Inflammatory and Cortical Responses after Transcranial Direct Current Stimulation in Disorders of Consciousness: An Exploratory Study.

Disorders of consciousness (DoC) due to severe traumatic brain injury (TBI) are associated with severe disability and an alteration of cortical activation, angiogenesis, and inflammation, which are crucial elements for behavioural recovery. This exploratory study aimed to evaluate anti-inflammatory and cortical responses after transcranial direct current stimulation (tDCS) in traumatic prolonged disorders of consciousness. Ten minimally conscious state (MCS) patients underwent ten sessions of anodal tDCS (five sessions/week, two weeks, 40 min/session) on the primary motor cortex bilaterally. Clinical evaluations were performed using the Coma Recovery Scale-Revised (CRS-R) pre- and post-treatment. In contrast, after single and multiple tDCS sessions, the haemodynamic cortical response was obtained with functional near-infrared spectroscopy (fNIRS). Moreover, angiogenesis (angiopoietin-2, BMP9, endoglin, HbEFG, HGF, IL8, Leptin, PLGF, VEGF-A, and VEGF-C) and inflammation (GM-CSF, IFNg, IP10, MCP1, and TNFα) circulating biomarkers were collected. A significant haemodynamic response was observed after a single tDCS session, with an increased activation from 4.4 (3.1-6.1) to 7.6 (2.9-15.7) a.u. (p = 0.035). After ten tDCS sessions, a significant reduction of angiopoietin-2, VEGF-C, and IP-10 was detected. Moreover, a correlation between behavioural (CRS-R), TNFα (r = 0.89; p = 0.007), and IP10 (r = 0.81; p = 0.014) variation was found. In conclusion, a single tDCS session can increase the cortical activation in MCS patients. Moreover, multiple tDCS sessions showed an anti-inflammatory effect related to behavioural improvement.

A novel immersive virtual reality environment for the motor rehabilitation of stroke patients: A feasibility study.

We designed and implemented an immersive virtual reality (VR) environment for upper limb rehabilitation, which possesses several notable features. First, by exploiting modern computer graphics its can present a variety of scenarios that make the rehabilitation routines challenging yet enjoyable for patients, thus enhancing their adherence to the therapy. Second, immersion in a virtual 3D space allows the patients to execute tasks that are closely related to everyday gestures, thus enhancing the transfer of the acquired motor skills to real-life routines. Third, in addition to the VR environment, we also developed a client app running on a PC that allows to monitor in real-time and remotely the patients' routines thus paving the way for telerehabilitation scenarios. Here, we report the results of a feasibility study in a cohort of 16 stroke patients. All our patients showed a high degree of comfort in our immersive VR system and they reported very high scores of ownership and agency in embodiment and satisfaction questionnaires. Furthermore, and notably, we found that behavioral performances in our VR tasks correlated with the patients' clinical scores (Fugl-Meyer scale) and they could thus be used to assess improvements during the rehabilitation program. While further studies are needed, our results clearly support the feasibility and effectiveness of VR-based motor rehabilitation processes.

Relation Between EEG Measures and Upper Limb Motor Recovery in Stroke Patients: A Scoping Review.

Current clinical practice does not leverage electroencephalography (EEG) measurements in stroke patients, despite its potential to contribute to post-stroke recovery predictions. We review the literature on the effectiveness of various quantitative and qualitative EEG-based measures after stroke as a tool to predict upper limb motor outcome, in relation to stroke timeframe and applied experimental tasks. Moreover, we aim to provide guidance on the use of EEG in the assessment of upper limb motor recovery after stroke, suggesting a high potential for some metrics in the appropriate context. We identified relevant papers (N = 16) from databases ScienceDirect, Web of Science and MEDLINE, and assessed their methodological quality with the Joanna Briggs Institute (JBI) Critical Appraisal. We applied the Preferred Reporting Systems for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) Framework. Identified works used EEG to identify properties including event-related activation, spectral power in physiologically relevant bands, symmetry in brain dynamics, functional connectivity, cortico-muscular coherence and rhythmic coordination. EEG was acquired in resting state or in relation to behavioural conditions. Motor outcome was mainly evaluated with the Upper Limb Fugl-Meyer Assessment. Despite great variability in the literature, data suggests that the most promising EEG quantifiers for predicting post-stroke motor outcome are event-related measures. Measures of spectral power in physiologically relevant bands and measures of brain symmetry also show promise. We suggest that EEG measures may improve our understanding of stroke brain dynamics during recovery, and contribute to establishing a functional prognosis and choosing the rehabilitation approach.

An energy-efficient in-memory computing architecture for survival data analysis based on resistive switching memories.

One of the objectives fostered in medical science is the so-called precision medicine, which requires the analysis of a large amount of survival data from patients to deeply understand treatment options. Tools like machine learning (ML) and deep neural networks are becoming a de-facto standard. Nowadays, computing facilities based on the Von Neumann architecture are devoted to these tasks, yet rapidly hitting a bottleneck in performance and energy efficiency. The in-memory computing (IMC) architecture emerged as a revolutionary approach to overcome that issue. In this work, we propose an IMC architecture based on resistive switching memory (RRAM) crossbar arrays to provide a convenient primitive for matrix-vector multiplication in a single computational step. This opens massive performance improvement in the acceleration of a neural network that is frequently used in survival analysis of biomedical records, namely the DeepSurv. We explored how the synaptic weights mapping strategy and the programming algorithms developed to counter RRAM non-idealities expose a performance/energy trade-off. Finally, we discussed how this application is tailored for the IMC architecture rather than being executed on commodity systems.

The Italian version of the Erasmus MC modifications to the Nottingham Sensory Assessment for patients following acquired brain injury: Translation and reliability study.

OBJECTIVE: To develop the Italian version of the Erasmus MC modifications to the Nottingham Sensory Assessment and to investigate its internal consistency, intra- and inter-rater reliability. DESIGN: Prospective cohort study. SETTING: Rehabilitation department. SUBJECTS: A total of 34 patients with acquired brain injury. MAIN MEASURE: The translation and cultural adaptation process was completed, and the testing procedures of the Italian version of the Erasmus MC modifications to the Nottingham Sensory Assessment were standardized. Internal consistency was evaluated using Cronbach's alpha index; assessment of intra- and inter-rater reliability was carried out using weighted kappa coefficient. RESULTS: The internal consistency of the tactile sensations and the proprioception items of the Italian version of the Erasmus MC modifications to the Nottingham Sensory Assessment were generally acceptable to excellent with a range of Cronbach's alpha between 0.73 and 0.97. The intra-rater reliability of the tactile sensations and the proprioception items of the Italian version of the Erasmus MC modifications to the Nottingham Sensory Assessment were generally good to excellent with a range of weighted kappa coefficients between 0.47 and 1.00. Likewise, the inter-rater reliabilities of these items were predominantly good to excellent with a range of weighted kappa coefficients between 0.42 and 0.92. CONCLUSION: The Italian version of the Erasmus MC modifications to the Nottingham Sensory Assessment is a reliable screening tool to evaluate primary somatosensory impairments in patients with acquired brain injury. Further research is necessary to consolidate these results and establish the validity and responsiveness of the Italian version of the Erasmus MC modifications to the Nottingham Sensory Assessment.

Construct Validity and Responsiveness of the COVID-19 Yorkshire Rehabilitation Scale (C19-YRS) in a Cohort of Italian Hospitalized COVID-19 Patients.

Post-COVID Syndrome (PCS) is characterized by physical, psychological and cognitive symptoms with a negative impact on daily activities. This study tested the responsiveness and construct validity of the original version of the COVID-19 Yorkshire Rehabilitation Scale (C19-YRS) in a cohort of Italian hospitalized COVID-19 patients. This longitudinal study involved 79 hospitalized COVID-19 patients with rehabilitation needs, assessed after 12 and 26 weeks post-infection. Functional and patient-reported outcome measures were correlated with 10 items of the C19-YRS to test the construct validity, whereas distribution-based methods were used for the responsiveness over time. After 12 weeks since infection, 88.5% of patients reported fatigue, 83.3% breathlessness, 69.4% anxiety, 55.6% depression, and 44.9% pain. Moreover, 84.6% experienced reduced mobility, 75.7% had difficulties with usual activities, and 47.4% with personal care. Single items for each symptom had significant correlation (rho 0.25-0.60) with well-established scales for these symptoms. At 26 weeks, except for anxiety, all the PCS symptoms were still present but significantly reduced. The C19-YRS had moderate responsiveness for the most represented deficit reported. The C19-YRS was a valuable patient-reported outcome for screening, assessing severity, and monitoring the persistence of symptoms after 12 and 26 weeks from SARS-CoV2 infection in a cohort of Italian hospitalized patients.

Combined effects of cerebellar tDCS and task-oriented circuit training in people with multiple sclerosis: A pilot randomized control trial.

BACKGROUND: Balance and mobility impairments are frequent in people with multiple sclerosis, partly due to cerebellar dysfunctions. Task-oriented behavioural approaches were previously shown to promote physical function. The possibility exists that cerebellar transcranial direct current stimulation (ctDCS) applied during training, known to increase the excitability of the brain, can boost rehabilitation effects through modulation of cerebellum-brain inhibition. OBJECTIVE: To test the efficacy of cerebellar ctDCS stimulation combined with motor training on mobility and balance in people with multiple sclerosis. METHODS: 16 subjects were randomly assigned to receive real- or sham-ctDCS and task-oriented training daily over two weeks in a double-blind, randomised clinical pilot trial. Functional mobility, balance, walking performance and quality of life were tested before and after treatment and at two-week follow-up. Effects of cerebellar stimulation on psychological and executive functions were also recorded. RESULTS: Walking performance, balance and quality of life improved for both groups at post-treatment assessment which was maintained at 2-weeks follow up. A two-way ANOVA revealed a significant time effect for balance and walking performance. A significant interaction effect of time-treatment (F = 3.12, df = 2,26; p = 0.03) was found for motor aspects of quality of life assessment in patients who received real-ctDCS. CONCLUSIONS: Task-oriented training improves balance and mobility in people with multiple sclerosis, but ctDCS does not boost motor training effects.

Cortical Oxygenation during a Motor Task to Evaluate Recovery in Subacute Stroke Patients: A Study with Near-Infrared Spectroscopy.

In subacute stroke patients we studied cortical oxygenation changes by near-infrared spectroscopy (NIRS) during a motor task performed with the hemiparetic arm (15 s of reaching and grasping, 45 s of rest, repeated 6 times). Twenty-three subjects were included at baseline, compared with six healthy subjects, and restudied after 6 weeks of rehabilitation. Motor/premotor cortical changes in oxyhemoglobin detected by NIRS were quantified as the area under the curve (AUC) for the total cortex (TOT-AUC) and for both affected (AFF-AUC) and unaffected hemispheres (UN-AUC). The ratio between AUC and the number of task repetitions performed identified the cortical metabolic cost (CMC) or the oxygenation increase for a single movement. Fugl−Meyer assessment of the upper extremity (FMA-UE) was also performed. At baseline, both total and hemispheric CMC were significantly higher in stroke patients than in healthy subjects and inversely correlated with FMA-UE. After rehabilitation, changes in total-CMC and unaffected-CMC, but not Affected-CMC, were inversely correlated with variations in the FMA-UE score. A value > 5000 a.u. for the ratio baseline TOT-CMC/days since stroke was associated with not reaching the clinically important difference for FMA-UE after rehabilitation. In subacute stroke the CMC, a biomarker assessed by NIRS during a motor task with the hemiparetic arm, may describe cortical time/treatment reorganization and favor patient selection for rehabilitation.

Combining a supervised and home-based task-oriented circuit training improves walking endurance in patients with multiple sclerosis. The MS_TOCT randomized-controlled trial.

BACKGROUND: Balance and mobility impairments are widespread in patients with Multiple Sclerosis (PwMS), even at an early stage. They can contribute to disability, physical deconditioning and reduced quality of life. Task-oriented is a training modality that may promote walking abilities and conditioning. However, the effects usually are short-lasting and exercising at home can have several barriers. This randomized controlled trial aimed to test the effectiveness of the combination of a 2-weeks in-person, supervised task-oriented circuit training (TOCT), followed by a 12-weeks home-based task-oriented program with monthly in-person visits. METHODS: 36 PwMS with EDSS 4-5.5 and unassisted walking have been randomly assigned to 10 supervised TOCT sessions over two weeks (Phase 1) followed by a 12-weeks home-based task-oriented program (Phase 2) or a delayed-treatment group. At the end of Phase 2, the delayed-treatment group (usual care) received the same TOCT protocol. Phase 1 was composed of six gait-based workstations and treadmill training, whereas Phase 2 was based on progressive task-oriented tasks practice at home with monthly visits to adjust activities levels. Six Minute Walk Test (6MWT), Timed 25-foot walk test (T25FW), Timed Up and Go test (TUG), Dynamic Gait Index (DGI), Modified Fatigue Impact Scale (MFIS), Multiple Sclerosis Walking Scale - 12 (MSWS-12), Multiple Sclerosis Impact Scale-29 (MSIS-29) and resting muscle oxygen consumption (rmVO2) were assessed as outcome measures at baseline, after Phase 1 and after Phase 2. Retention was tested on the whole sample at a 12-weeks follow-up. RESULTS: The entire sample completed the 2-weeks TOCT, whereas adherence was good for the 12-weeks home-based task-oriented program (6.2/10). The mean repetitions and level of difficulty of each task significantly increased after every timepoint. A superiority of task-oriented program was verified for 6MWT (F, 2,88 = 7.80; p<0.001) on usual care after the 12-weeks home-based program. Moreover, between-group differences were highlighted at the same point, even for T25FW, TUG and MSWS-12. RmVO2 and fatigue were significantly improved only in the experimental group. Positive effects on 6MWT were retained 12 weeks after the end of the protocol (p<0.001) in the whole sample. CONCLUSIONS: The combination of a supervised and self-managed task-oriented program enhances walking endurance with positive effects on walking ability, fatigue and resting muscle oxygen consumption in PwMS with unassisted walking. These preliminary results reflected how this intervention was effective for impairment and activity improvements; moreover, it was cardiorespiratory stressful and possibly reduced deconditioning.