People affected by Stroke, Multiple Sclerosis (MS), and Parkinson's disease (PD) share severe and complex disabilities. Widespread neuro-inflammatory processes represent an important pathogenetic component in all three conditions. The potential overlap with neurological complications of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection has further contributed to the worsening of functional impairment. Since pharmacological therapies have limited or negligible effects in these disorders, neurorehabilitation plays a crucial role in restoring and maintaining adequate functional abilities. In this context, dual-task strategies have attracted growing interest, but their effectiveness has not been adequately assessed in the above neurological conditions-and not at all in individuals with long-term sequelae of SARS-CoV-2 infection.

Based on these premises, the objectives of this research project are:

• to design rehabilitation strategies using the dual-task approach in its various forms (dual motor task, dual cognitive task, and combined motor-cognitive task) and to conduct feasibility tests in small groups of individuals affected by stroke, MS, PD, or long-term Coronavirus Disease 2019 (COVID-19) sequelae;
• to apply the strategies found to be effective in larger trials involving participants with stroke, MS, or PD, with or without a history of SARS-CoV-2 infection;
• to compare the outcomes of dual-task strategies with those obtained through conventional rehabilitation approaches.

The activities planned within the project will be distributed among the four participating operating units (OUs). OU1 (Santa Lucia Foundation) will be responsible for:

1. designing and validating dual-task rehabilitation strategies covering the three possible combinations of motor and cognitive activities (dual motor task, dual cognitive task, and combined motor-cognitive task);
2. assessing the feasibility of these strategies through a pilot study involving small groups of individuals with the aforementioned neurological conditions, including those with long-term outcomes of SARS-CoV-2 infection, and selecting the most suitable approaches.

All four OUs will participate in the selection and enrollment of subjects for the trial phase.

OUs 1, 3, and 4 (Collaborators to the project) will conduct the activities planned for the experimental trial, including:

1. baseline assessment of enrolled participants using validated instruments to measure various motor and cognitive functions;
2. implementation of rehabilitation strategies based on the dual-task approach, making use of newly emerging technological devices;
3. follow-up assessments at the end of the treatment period and again three months later.

Assessments will focus on motor functions such as gait and balance, cognitive functions, mood, the occurrence of domestic accidents, and the measurement of circulating biomarkers of neuroinflammation and neurodegeneration.

Data collected throughout the different phases of the study will be compiled into a single database, and statistical analyses will be performed by researchers from OU1.

The interpretation of results will be carried out collaboratively by members of all OUs, and findings will be disseminated through participation in conferences and congresses, as well as through publications in peer-reviewed international indexed journals.

Summary Description

Neurological diseases such as Stroke Outcomes (SO), Multiple Sclerosis (MS), and Parkinson's disease (PD) cause complex and severe disabilities involving motor, cognitive, and autonomic domains. Widespread neuroinflammation contributes to progressive tissue damage in all three conditions. SARS-CoV-2 infection can further exacerbate neurological deficits through inflammatory mechanisms, and its long-term effects may aggravate pre-existing motor and cognitive impairments. Pharmacological therapies for these diseases-and for post-COVID neurological sequelae-offer limited benefit; therefore, neurorehabilitation represents a crucial therapeutic resource.

Dual-task approaches, which simultaneously target cognitive and motor functions, have gained increasing interest because they better reflect daily life demands, align with embodied cognition theories, and allow concurrent intervention on multiple deficit domains. However, their efficacy has not been adequately assessed in SO, MS, and PD, and has not been investigated at all in individuals with long-term neurological consequences of SARS-CoV-2. This project aims to design and validate dual-task rehabilitation strategies in these populations and compare their outcomes with those of conventional rehabilitation.

Background and State of the Art

Individuals with SO, MS, and PD share multifaceted disabilities and underlying neuroinflammatory processes. The additional impact of COVID-19, especially in cases with persistent neurological manifestations, emphasizes the urgency of effective rehabilitation methods. Preliminary work by the research team includes studies on dual-task mechanisms and implementation in clinical settings, confirming feasibility and theoretical relevance. Nonetheless, rigorous randomized, controlled-possibly double-blind-trials are required to determine clinical efficacy.

Project Activities and Organization

The project includes the following integrated activities:

Design and validation of dual-task rehabilitation strategies, encompassing:

• dual motor tasks
• dual cognitive tasks
• combined motor-cognitive tasks Virtual and/or augmented reality environments will be used when beneficial. Pilot feasibility study in small groups (5 per diagnostic category: SO, MS, PD, long-term post-COVID) to assess applicability, patient acceptance, and preliminary efficacy. Conducted by OU1.

Participant selection for the clinical trial (SO, MS, PD, with or without past SARS-CoV-2 infection) based on predefined inclusion/exclusion criteria. Conducted jointly by all OUs.

Randomized controlled trial, conducted by OU1, OU3, and OU4, including:

1. Baseline motor, cognitive, and mood assessment using validated tools.
2. Implementation of dual-task strategies alongside standard rehabilitation, using emerging technological devices.
3. Re-assessment at treatment completion and at 3-month follow-up.

Data integration in a unified database (OU1). Statistical analyses and interpretation, including advanced methods such as artificial neural networks (OU1).

Dissemination through conferences and publications. Specific Aims Aim 1 - Development and feasibility testing of dual-task strategies

Dual-task interventions will be designed by OU1 based on the three task combinations. A preliminary feasibility phase will enroll 20 participants (5 SO, 5 MS, 5 PD, 5 post-COVID). Strategies demonstrating the best balance of efficacy and acceptability will be selected for the clinical trial.

Aim 2 - Application of validated strategies in a randomized controlled trial A total of 48 participants (16 SO, 16 MS, 16 PD) will be recruited; for each condition, half will have a history of SARS-CoV-2 infection with neurological symptoms persisting ≥4 weeks. Additional inclusion/exclusion criteria ensure safety and feasibility.

Participants will be randomized into:

• Experimental group: standard rehabilitation (3/week) with dual-task training (2/week, 30 min/session)
• Control group: standard rehabilitation with placebo low-resistance cycling (2/week, 30 min/session)

Aim 3 - Comparison of dual-task vs conventional rehabilitation outcomes

Outcome measures will be compared between:

• participants receiving standard with placebo therapy, and
• participants receiving standard with dual-task therapy.

Additionally, pre- and post-intervention blood samples will be analyzed for biomarkers of neuroinflammation and neurodegeneration, providing complementary insight into physiological changes associated with both rehabilitation modalities.

Appropriate statistical methods, including machine-learning-based analyses, will be used to evaluate between-group and within-group differences.

Inclusion Criteria:

• Diagnosis of stroke outcomes, Multiple Sclerosis (MS), or Parkinson's disease (PD).
• For stroke outcomes: patients must be able to walk independently for at least 6 minutes without resting.
• For MS: diagnosis according to the 2017 revised McDonald criteria; relapsing-remitting or secondary progressive forms; age 25-65 years; Expanded Disability Status Scale score between 2.5 and 6.0.
• For PD: idiopathic Parkinson's disease.
• For each neurological condition, half of the participants must have had Severe Acute Respiratory Syndrome Coronavirus 2 infection with neurological symptoms attributable to CNS involvement lasting at least 4 weeks.
• Ability to provide informed consent.

Exclusion Criteria:

• Cognitive or motor comobidity;
• Severe visual or hearing impairments that may compromise understanding of exercises
• Language impairments, such as aphasia
• Inability to walk independently