BACKGROUND:Dual-task activities are frequently impaired in people with MS (PwMS), with a high impact on daily life activities. Exergaming may represent a valuable treatment for dual-task abilities as it involves motor and cognitive task. AIM:To evaluate whether a video game training (VGT) improves mobility, balance, cognitive functions, and dual tasking more than a standardized balance platform training (BPT). DESIGN:Single-blinded, randomized control trial. SETTING:Outpatient. POPULATION:People with multiple sclerosis (PwMS). METHODS:Forty-eight PwMS were allocated to either VGT or BPT group. VGT was delivered using a commercially available video game console, BPT using a rehabilitative balance platform. Both groups received twelve 1-hour sessions over four weeks. All subjects were evaluated before (T0), after treatment (T1) and at the three-month follow-up (T2). The primary outcome was functional mobility assessed with the Timed Up and Go test. Secondary outcomes included balance, patient-reported measures, cognitive functions, and posturographic assessment in single and dual-task condition. RESULTS:Mobility significantly improved after treatment in the BPT group. Fatigue and perceived walking ability improved after treatment only in the VGT group. Both treatments significantly improved static and dynamic balance (after treatment and at the three-month follow-up) and quality of life (after treatment). Between-group analysis revealed a significant improvement in reaction time only in people who received VGT. CONCLUSIONS:Both VGT and BPT were effective in improving balance and quality of life in PwMS. Although no changes in dual-task performance were observed, VGT led to specific improvements in attentional performance. CLINICAL REHABILITATION IMPACT:Video game rehabilitation may offer a useful and engaging option for improving balance, quality of life, and attention in PwMS. As no improvements were found in dual-task performance, longer-term studies are needed before conclusions can be drawn about its broader rehabilitative impact.

Background: MiRNAs within extracellular vesicles can encompass body barriers, reflecting stage, progression, and response to treatments of various diseases, including multiple sclerosis (MS)—a chronic immune-mediated disease of the central nervous system that causes progressive disability, with highly variable clinical courses. In this context, urinary exosomal miRNAs could be an appealing source of biomarkers, thanks to their non-invasive and easily repeatable collection. Methods: In this exploratory investigation, we tried to assess if profiling urinary exosomal miRNAs could reveal subtle differences within an apparently homogeneous MS population. The study involved 24 patients with primary or secondary progressive MS, whose urinary exosomes (UEs) were subjected to evaluation of a panel of 87 miRNAs variously correlated with neuroinflammation, cardiovascular functions, and/or involved in MS. Results: We revealed that the examined miRNAs were heterogeneously expressed across the patients, reflecting, as expected, their gender and/or hormonal status. Two miRNAs discriminated against primary or secondary progressive MS, and a panel of 14 commonly upmodulated miRNAs identified patients with longer disease duration and a greater degree of disability. Conclusions: Even if preliminary, these data represent the first relationship between UEs and MS features in humans and suggest that urine could constitute a non-invasive source of exosomal miRNAs, which could prove useful in complementing conventional monitoring to provide a more personalized management of MS patients.

Matching brain stimulation to the brain's natural rhythms can drive plasticity, yet this principle has rarely been tested in humans. We targeted the cerebellum, a key hub for motor coordination and learning, using a rhythm-tuned protocol that pairs theta-frequency transcranial alternating current stimulation with intermittent theta-burst stimulation to engage plasticity of cerebello-cortical circuits. In young healthy adults, this pairing enhanced fine motor control and hand dexterity, with gains closely tracking physiological markers of cerebellar-driven plasticity. Applying the same approach in chronic stroke survivors yielded parallel behavioral and neural gains, demonstrating preserved rhythm-plasticity coupling despite injury. Control experiments confirmed both frequency specificity and site specificity, underscoring the mechanistic precision of the intervention. By linking theta-frequency cerebellar stimulation to circuit-level and functional outcomes, these findings establish a biologically grounded framework for targeted neurorehabilitation. Rhythm-specific cerebellar stimulation provides a scalable strategy for enhancing plasticity and improving motor function across movement disorders and motor impairments.

BACKGROUND:The integration of innovative technologies in Physical and Rehabilitation Medicine (PRM) has significantly advanced patient care, enhancing functional recovery and optimizing rehabilitation processes. Despite growing clinical adoption, a translational gap persists between technological advancements and routine clinical implementation. This study aims to map the available evidence on rehabilitation technologies, identifying their applications, effectiveness, and existing limitations. METHODS:A mapping review of systematic reviews was conducted to explore the role of technological innovations in PRM. A systematic search of the MEDLINE (PubMed) database was performed up to July 14th, 2024. Eligible studies were screened based on predefined inclusion and exclusion criteria. Data extraction focused on rehabilitation domains, technological interventions, target populations, and Health Technology Assessment (HTA) aspects. RESULTS:Of 5124 identified records, 623 systematic reviews (12.2%) met the inclusion criteria. Neurological conditions represented the primary focus (56.8%), followed by musculoskeletal (23.7%) and cardiovascular rehabilitation (11.5%). The most frequently studied technologies included virtual reality (28.5%), non-invasive brain stimulation (18.7%), robotics (16.3%), and telerehabilitation (13.4%). Most studies assessed motor recovery (45%), pain management (22%), and cognitive or language rehabilitation (18%). Only 4.8% addressed HTA aspects such as cost-effectiveness and acceptability, highlighting a gap in real-world implementation studies. CONCLUSIONS:This mapping review underscores the increasing interest in technology-assisted rehabilitation but also highlights critical gaps, particularly in HTA assessments and training for PRM specialists. Standardized guidelines, structured training programs, and economic evaluations are essential to optimize integrating rehabilitation technologies into clinical practice. Further research should focus on long-term efficacy, accessibility, and sustainability to ensure equitable access to innovative rehabilitation solutions.

Stroke survivors often experience balance impairments which may result in increased risk of falling. However, it is unclear whether and how a stroke changes cortical involvement for postural control. To clarify this issue, we assessed the effect of stroke on sway-based corticokinematic coherence (CKC), which is a measure of the coupling between cortical electrophysiological signals and postural sways. To that end, we recorded the center-of-pressure fluctuations and electroencephalographic cortical activity of 34 stroke survivors and 34 healthy participants performing balance tasks during which sensory information was manipulated, by either removal or alteration. We found significantly increased CKC derived from medio-lateral sway in stroke participants when standing on foam compared to healthy controls, suggesting an increase in cortical involvement to compensate for the decreased function of the hemiparetic side, even in highly functional stroke survivors. Moreover, a relationship was found between CKC and clinical scores (Berg Balance Scale and Fugl-Meyer). This suggests that CKC could be used as a biomarker to track progress beyond traditional functional recovery as measured by clinical scores.

BACKGROUND:Robot-assisted therapy (RAT) with exoskeletons is believed to enhance motor recovery in stroke survivors. RAT offers intensive, feedback-based, task-oriented training to improve function. This study evaluated exoskeleton-based RAT integrated into usual rehabilitation care for individuals in early subacute stroke. METHODS:This multicenter randomized controlled trial was conducted across 8 stroke neurorehabilitation units over a 3-year period (December 2020-March 2024). Inpatients with moderate-to-severe upper limb impairment postsubacute stroke (<3 months poststroke) were randomized (1:1) to 25 sessions (5/week for 5 weeks) of exoskeleton-assisted RAT (robotic group) or conventional rehabilitation (control group). Outcome assessors were blinded. The primary outcome was the change in the Fugl-Meyer Assessment for Upper Limb (motor section, 0-66) from baseline to treatment end. Secondary outcomes addressed body function, activity (capacity/performance), and participation. Clinical assessments were at baseline (T0), posttreatment (T1), and 6-month telephone follow-up (T2). Odds ratio for achieving a minimal clinically important difference (≥10 points) on the Fugl-Meyer Assessment for Upper Limb was calculated. RESULTS:A total of 109 individuals with subacute stroke were screened. Of these, 94 (35% women; mean age 62.5±13.5 years; mean onset 34±28 days) were eligible and randomized, and 82 completed the intervention (12% dropout). No significant differences were observed at baseline, despite the median Fugl-Meyer score being 16 in the robotic group and 10 in the control group. The robotic group showed significantly greater improvement in Fugl-Meyer Assessment for Upper Limb motor score than the control group, with a median between-group difference of 22 points (P<0.001). Minimal clinically important difference was reached by 68.4% in the robotic group versus 31.8% in the control group (odds ratio, 4.64 [95% CI, 1.83-11.8]; P<0.001). All secondary outcomes improved significantly in both groups with no significant differences between groups, except for spasticity, which showed no significant change. CONCLUSIONS:Exoskeleton-assisted RAT offers significant clinical benefits in early poststroke upper limb recovery, yielding higher minimal clinically important difference rates on impairment outcomes but not on specific functional measures compared with conventional therapy. Further research should evaluate long-term effects and optimize protocols based on patient characteristics. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04697368.

Background: Restoring motor function is crucial for daily life after a stroke. Although patients’ engagement and attention influence motor recovery, these factors are frequently overlooked in rehabilitation interventions. Methods: This prospective open-label pilot trial (NCT04622189) investigated the impact of attentional deficits on engagement and motor recovery in 10 subacute stroke patients undergoing a 4-week action observation training program. At baseline, they were divided into two subgroups based on attentional performance, as determined by scores on the Test of Attentional Performance (subtests of divided attention and Go/No-Go): those with attention deficits (AD, i.e., deficits in one or both tasks, n = 6) and those without (No_AD, no deficits in either task, n = 4). Results: Both groups exhibited similar motor profiles at baseline; however, the AD group presented significantly lower cognitive reserve (AD mean (SD) 92.2 ± 4.09, No_AD 120 ± 14.9, p = 0.005) and greater anxiety and depressive symptoms (AD 66.7%, No_AD 0%, p = 0.035). While all patients showed improvements in motor outcomes, the No_AD group demonstrated significantly greater gains in upper limb function, as assessed by the Fugl-Meyer Assessment (AD 3.33 ± 1.21, No_AD 10.8 ± 5.7, p = 0.013). Engagement and accuracy of interactive questions, used as proxies for concentration during training, were also higher in the No_AD group and positively correlated (rho = 0.9075, p ≤ 0.001). Moreover, patients with attention deficits reported lower levels of engagement during training. Conclusions: These findings indicate that attentional status may affect both adherence to and responsiveness to rehabilitation. This highlights a potentially relevant factor to consider when improving post-stroke interventions.

BACKGROUND:Robot-assisted gait training (RAGT) is an effective strategy for rehabilitation of people with MS (PwMS) and severe gait impairment, but the optimal training parameters remain undefined. The use in continuous mode may impose high internal load and physiological stress, potentially limiting its wide applicability. OBJECTIVE:To evaluate whether a low-intensity RAGT at progressively increasing intensity (LowRAGT) improves walking function more than continuous RAGT or self-paced overground gait training (OGT). METHODS:We conducted a three-group parallel-assignment pilot, double-blinded, randomized control trial in which 24 PwMS were allocated to either LowRAGT or RAGT or OGT group, after receiving two hours of conventional rehabilitative programme. The primary outcome was gait speed assessed with the Timed 25-Foot Walk test before and after the treatment and at three-month follow-up. Secondary outcomes were mobility, endurance, balance, and patient-reported outcome measures (PROMs). RESULTS:Gait speed significantly improved after treatment in the LowRAGT (+31 %, p = 0.03) and OGT (+7 %, p = 0.04). No improvements were retained at the three-month follow-up. Only the LowRAGT retained the improvement in mobility, endurance and balance at the follow-up. No changes were observed in PROMs. CONCLUSIONS:A LowRAGT is effective in improving gait speed in PwMS and allows the long-term retention of mobility, endurance and balance improvements. TRIAL REGISTRATION:ClinicalTrials.gov (NCT06381440).

Patients in a minimally conscious state (MCS) are characterized by behavioral signs of self- or environmental-awareness. EEG oscillations in MCS are known slowing down. Neuroelectrical modulations of MCS intervention – e.g., transcranial direct current stimulation (tDCS) – are assessed using EEG features, and related to clinical scores. However, these features are handcrafted in a non-patient-specific way. Conversely, interpretable and explainable artificial intelligence (IXAI) automatically extracts the most salient patient-specific features. In this pilot study, we use IXAI for tracking the EEG changes of 9 MCS patients following tDCS. Our approach is composed by an interpretable neural network (Sinc-ShallowNet) and an explanation technique (DeepLIFT). The network discriminates resting-state EEG before vs. after tDCS and learns interpretable spectral features; DeepLIFT quantifies the relevance of the frequency components. Patients with higher neurobehavioral improvements show a maximum relevance at high frequencies (high-alpha) and a minimum at low frequencies (delta); vice versa for patients with lower improvements. Our results corroborate the idea that tDCS could support MCS intervention, and that IXAI could be useful, prospectively, to design patient-specific markers tracking the effects of intervention.

The combination of chronic kidney disease (CKD) and peripheral artery disease (PAD) enhances the already present high cardiovascular risk, exposing the affected patients to unfavourable long-term clinical outcomes. Physical exercise is considered an effective treatment for reducing sedentary behaviour and improving quality of life, but several barriers limit patient participation. In this parallel-design, single-blinded, randomised controlled trial, we will enrol 130 patients with concomitant CKD at stages III and IV and PAD at the claudication stage to be randomised into a 6-month exercise (Ex) or control (Co) intervention. The Ex programme will consist of two daily 10 min interval walking sessions (1 min of walking followed by 1 min of resting), with gait speed controlled via a metronome and increased approximately weekly. The Co group will receive standard nephrological care. Outcomes will be assessed before and after treatment, as well as at the 12-month follow-up. The primary outcome will be the 6 min walking distance. The secondary outcomes will include quality of life, lower limb and handgrip strength, body composition and bone mineral density, as well as circulating indexes of kidney function and long-term clinical outcomes. Since no trials have been published that purposely enrol this high-risk population (CKD-PAD), the eventual positive results will validate a simple, pain-free exercise intervention that can be carried out at home to improve patients’ mobility and quality of life. Trial registration number: NCT06621264.

Paired Associative Stimulation (PAS) protocols have been widely employed to study functional neural connections along the cortico-spinal pathways and between interconnected brain regions. PAS protocols induce spike-timing-dependent plasticity, underscoring their potential as therapeutic neurostimulation tools. Cortico-peripheral PAS is based on the temporal pairing of peripheral nerve stimulation (PNS) and cortical transcranial magnetic stimulation (TMS) pulses, applied repeatedly at specific inter-stimulus intervals, to modulate the activity of the corticospinal tract. In contrast, cortico-cortical PAS involves the application of TMS pulses at two different brain areas to induce long-term changes in functional connectivity. In this review, we provide a comprehensive overview of existing PAS protocols and the factors influencing their effects, with particular emphasis on the critical role of the inter-stimulus interval. We trace the development of PAS from initial experiments in healthy subjects to its emerging therapeutic applications in various pathological conditions. We summarize current preliminary findings, discuss limitations, outline future directions, and review ongoing clinical trials. Although still in its early stages, PAS, particularly cortico-peripheral PAS, shows promising efficacy in motor recovery for stroke and spinal cord injury patients. Furthermore, initial evidence points to potential benefits in Alzheimer's disease and generalized anxiety disorders, supporting the expanding therapeutic scope of PAS protocols.

Objectives To investigate the feasibility of employing socially assistive robots (SARs) as a means to enhance compliance with home-based rehabilitation programs among children with neurologic conditions such as cerebral palsy. Design A prototype version of the REHAB-PAL system was created by integrating both an active video game (AVG) interface and an SAR, specifically the Nao robot. Setting Rehabilitation hospital. Participants We recruited 10 children with neurologic conditions (7-14 years old, 4 boys and 6 girls). Interventions Participants engaged in AVG games targeting gait and balance under 3 distinct conditions. These conditions were randomly assigned to each participant and included: (1) utilizing the AVG platform without any augmentation; (2) utilizing the AVG platform enhanced with a physically embodied SAR; and (3) utilizing the AVG platform enhanced with a virtual agent (an avatar displayed on the screen providing feedback similar to the SAR). After the session, both the child and parent(s) who attended the session were presented with questionnaires for feedback. Main Outcome Measures The primary outcome measure used was the system usability scale (SUS), employed to assess the system's usability. Results The results from the SUS indicate notable preferences for the SARs over both the virtual agent and the AVG platform in several key aspects. When comparing SAR to the virtual agent, participants expressed a strong inclination toward using the system frequently (90%) and perceived less complexity in its operation (70%). Additionally, a significant majority believed that most users would quickly grasp the system (90%) and found it less cumbersome to use (80%) compared to the virtual agent. When contrasting SAR with the AVG platform, participants favored SAR in terms of frequency of use (90%) and perceived complexity (90%). Conclusions Our study investigated the feasibility of utilizing SARs to enhance compliance with home-based rehabilitation programs among children with neurologic conditions, such as cerebral palsy. Through the integration of an AVG interface with a physically embodied SAR within the REHAB-PAL system, we aimed to create an engaging and supportive therapeutic environment. The findings, as assessed by the SUS, revealed significant preferences for SARs over both the virtual agent and standalone AVG platforms across various usability metrics. These results highlight the potential of SARs to improve the effectiveness and acceptability of home-based rehabilitation interventions for children with neurologic conditions. This research provides valuable insights for future studies and clinical applications aiming to enhance rehabilitation outcomes through innovative technology integration. Disclosures none.

Investigating how cognitive and motor functions interact in people with multiple sclerosis (PwMS) is key to identifying disease-related alterations, yet technical challenges have long hindered this research. We introduce an innovative framework for dual-task (DT) assessment in PwMS, integrating wearable electroencephalography (EEG) and inertial measurement unit (IMU) sensors. The study involved 11 PwMS (6 males, 5 females; mean age: 58.5 ± 12.5 years), who performed the timed up and go (TUG) test under two conditions: a motor task as single-task (ST) and a motor-cognitive DT. A custom-made bracelet including an IMU and a wearable EEG device allowed the recording of motion data and brain activity during the tasks. The former was used for automatic trial segmentation through a hybrid convolutional neural network and a long-shortterm-memory model. This allowed the extraction of the EEG epoch during the task. Finally, the power spectral density in θ (4-8 Hz) and α (8-12 Hz) frequency bands was analyzed to extract mental workload. The proposed segmentation method achieved accurate estimations when compared to manual video-based labeling, with a very strong correlation R2=0.993 and mean-absolute-error of 0.383 s and 0.294 s for the ST and DT conditions, respectively. The EEG results showed increased mental workload during the DT condition (Wilcoxon signed-rank test p-value = 0.02). The planned inclusion of new participants will help to confirm the robustness of cortical activity patterns during DT performances in PwMS.Clinical relevance—The proposed experimental protocol represents a significant step forward to the understanding of neural correlates of cognitive-motor interaction, allowing the recording of cortical activity during walking. These findings could contribute to a better understanding of the association between DT performance and risk of falls in PwMS and help design specific and personalized rehabilitation interventions.

OBJECTIVE:To investigate the feasibility and measurement properties of measurement tools for remote evaluation of motor performance in people with neurologic conditions requiring only synchronous or asynchronous video conferencing without sensors or other complex technological tools. DATA SOURCES:A systematic search was conducted in PubMed, Embase, the Cumulative Index for Nursing and Allied Health Literature (CINHAL), and ScienceDirect. The search strategy included keywords related to any neurologic population, telerehabilitation, and motor performance outcome measure; papers in Italian or English language on adults were included, without time restrictions. STUDY SELECTION:We included studies reporting data of at least one measurement property between reliability, validity, feasibility, or acceptability of measurement tools for remote motor assessment in neurologic disorders. We excluded studies that used wearable technologies, smartphones, or mobile applications. After duplicate removal, 2530 records were screened. Of the 461 remaining papers, 26 met the inclusion criteria and were included in the systematic review. DATA EXTRACTION:Two independent reviewers extracted data from the included records, evaluated the risk of bias of the studies using the Consensus-based Standards for the selection of health Measurement Instruments tool, and applied the criteria for good measurement properties and clinical utility. Discordance was solved through discussion with a third reviewer. DATA SYNTHESIS:Twenty-nine measurement tools were identified, and a narrative synthesis was conducted because of the heterogeneity of the included studies. The Fugl-Meyer Assessment for the Lower and Upper Extremity and the Tinetti Performance-Oriented Mobility Assessment Balance were suggested for the remote evaluation of people with stroke, whereas the Five Times Sit-to-Stand Test, the Nine-Hole Peg Test, and the Timed 25-Foot Walk Test were suggested for people with multiple sclerosis. CONCLUSIONS:Several measurement tools have been identified for remote evaluation of motor performance in people with neurologic disorders, but few of them can be suggested for clinical and scientific purposes. A higher methodological quality of studies would support the use of these tools in clinical practice.

OBJECTIVES:There is tentative evidence to support the analgesic effects of noninvasive brain stimulation (NiBS) in fibromyalgia (FM), but a comprehensive synthesis is lacking. This systematic review with network meta-analysis (NMA) aimed to determine the relative effectiveness of different NiBS techniques, such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) in FM, and to identify the optimal stimulation location and intensity/frequency. METHODS:Four databases were searched until July 9, 2023 for randomized trials (RCTs) comparing NiBS in FM. Pain was the primary outcome, while fatigue and sleep were secondary outcomes. A frequentist NMA calculated standardized-mean-differences (SMDs) for pain, with pairwise meta-analysis for fatigue and sleep. Bias was assessed with the Cochrane-risk-of-bias-tool (RoB-2.0), and evidence certainty through confidence-in-NMA. RESULTS:Forty-three RCTs with 2120 participants were included. NMA showed that low frequency (LF)-rTMS (SMD: -1.20, 95% CI: -1.82 to -0.58), dual tDCS (SMD: -0.91, 95% CI: -1.82 to -0.58), and high frequency (HF)-rTMS (SMD: -0.58, 95% CI: -1.00 to -0.17) likely results in a reduction in pain intensity at the end of intervention compared with sham stimulation. For stimulation location, right dorsolateral prefrontal cortex (DLPFC)(SMD: -1.42, 95% CI: -2.69 to -0.15), bilateral DLPFC (SMD: -0.94, 95% CI: -1.82 to -0.05), and left primary motor cortex (M1)(SMD: -0.49, 95% CI: -0.85 to -0.14) likely results in reduction in pain intensity at the end of intervention, with DLPFC maintaining effects in short-term. LF-rTMS over DLPFC (SMD: -1.42, 95% CI: -2.69 to -0.15) and HF-rTMS over M1 (SMD: -0.78, 95% CI: -1.39 to -0.18) likely results in the reduction in pain intensity at the end of intervention, with LF-rTMS over right DLPFC maintaining effects in the short term. NiBS appears to be safe and may reduce fatigue and improve sleep quality. DISCUSSION:Excitatory stimulation like HF-rTMS over M1 and inhibitory like LF-rTMS over DLPFC may yield better results.

Background/Objectives: We aimed to test whether home-based low-intensity interval training (LIIT) could be equally or more effective than traditional continuous walking advice (TWA) in a population hospitalized and healed from severe COVID-19. Methods: This pragmatic nonrandomized controlled trial (NCT04615390) enrolled patients admitted to intensive care units due to COVID-19 who at discharge from the hospital were given a choice between either a home-based LIIT program or TWA. The former received a structured LIIT walking (1:1 walk:rest ratio per 10 times) to be performed at a prescribed progressively increasing speed maintained with a metronome. The latter received TWA according to the guidelines (30 min or moderate intensity activity, 5 days/week). Outcome measures, collected at baseline, at the end of the 3-month training and at the 6-month follow-up, included 6 min walking distance (primary), lower limb strength, quality of life, depression and cognitive status. Results: From a total of 85 enrolled patients, 69 of them (LIIT n = 32; TWA n = 37) completed the study. Home exercise was safely executed with an 82% adherence for the LIIT group and 64% adherence for TWA. After the 3-month program, both groups significantly improved the 6MWD (LIIT: +87 m vs. TWA +42 m; p < 0.001) with a significant difference that was also maintained at follow-up (LIIT: +138 m vs. TWA +69 m; p < 0.001). No other significant between-group differences were noted. However, patients in the LIIT group significantly improved in the majority of the outcomes, while patients of TWA improved in only the primary outcome and the physical component of quality of life. Conclusions: Compared with TWA, LIIT walking was feasible, safe and associated with more favorable multidimensional recovery in COVID-19 survivors after hospitalization for severe pneumonitis.