Virtual Reality vs Traditional Cognitive Training in Patients With Severe Acquired Brain Injury (VR-sABI)

Multicentric Study on Implementation of Virtual Reality for Rehabilitation of Cognitive Functions in Patients With Severe Acquired Brain Injury: a Randomized Controlled Trial

Considerable evidence exists for using Virtual Reality (VR) for rehabilitation of acquired brain injury (ABI), with a particular focus on stroke. However, to date very little evidence has been collected in patients with ABI with different aetiologies (i.e., traumatic or anoxic brain injury) and level of severity (i.e., severe, sABI). The present multicentre study aims to overcome current literature issues as heterogeneity of populations and outcomes, small sample sizes and a lack of randomized controlled trials, which can affect the level of evidence and generalizability of results, to determine the effectiveness of a non immersive VR-based rehabilitation versus traditional cognitive training (TCT).

Study Overview

• Status: Recruiting
• Conditions: Acquired Brain Injury
• Intervention / Treatment: Device: Khymeia®-Virtual Reality rehabilitation System (VRRS EVO SYSTEM or COMPACT VRRS ENGINE); Behavioral: Traditional cognitive training (TCT)

Detailed Description

Background Virtual Reality (VR) refers to a computer-generated digital environment that can be experienced and interacted with as if that environment were real. VR systems are typically classified as immersive, semi-immersive, or non-immersive, with immersion referring to the level of user perception with regard to being in a virtual environment (VE) rather than the real world: immersive VR systems supply VEs with a changing field of view via head-mounted displays, and in which movement is achieved via hardware such as head trackers, hand controllers, and body motion sensors; semi-immersive VR refers to systems that use projection-based systems (e.g., driving simulators and use of shutter glasses); non-immersive VR systems include basic desktop displays and videogames.

Considerable evidence exists for using VR for rehabilitation of acquired brain injury (ABI), with a particular focus on stroke. The benefits of VR for ABI rehabilitation seem to include enhanced ecological validity, the ability to maintain experimental control over assessment and treatment standardization, and the control of task complexity. Indeed, VR can provide relatively naturalistic VEs for repeated practice of functional tasks such as activities of (instrumental) daily living which may assist with generalizing targeted skills. VR can also enhance patient motivation and active participation thanks to visual and auditory feedback, which is necessary for neurorehabilitation. Furthermore, VR tools offer the possibility to adapt the exercises to the patient's capabilities and needs and monitor their performance.

However, to date very little evidence has been collected in patients with ABI with different aetiologies (i.e., traumatic or anoxic brain injury) and level of severity (i.e., sABI). Moreover, current evidence provides some support for using VR for ABI rehabilitation, but the quality of the evidence is relatively low, and many studies include non-immersive and semi-immersive systems rather than focusing on immersive VR technology. For instance, a recent study44 investigated the effects of non-immersive VR-based training to improve executive abilities in patients with moderate to severe traumatic brain injury (TBI). Executive dysfunction is among the most common facets of cognitive impairment following TBI, involving about 48% of moderate-to-severe TBI patients. Patients received either the standard cognitive training (i.e., paper and pencil) or the VR-based cognitive training. The authors found that all patients improved their global cognitive and executive function, even though those treated with VR achieved better outcomes44. Although this study showed that VR cognitive rehabilitation can be a promising tool to improve executive functions, further studies are needed to confirm the value of VR in sABI. The present multicentre study aims to overcome current literature issues as heterogeneity of populations and outcomes, small sample sizes and a lack of randomized controlled trials, which can affect the level of evidence and generalizability of results.

Methods Study type: interventional Allocation: randomized Intervention model: parallel assignment (1:1) 28 patients will be randomly assigned to receive either 30 minutes of VR or TCT sessions at the same time each day throughout the experiment. 20 VR or TCT sessions will be applied, 5 per week for 5 weeks. Both groups will receive an additional 60 minute-comprehensive daily rehabilitation programme in the 3 months of the study. This programme consists of active limb mobilization, training on different cognitive domains, occupational therapy, language and swallowing therapy based on the patient's functional condition.

Primary endpoint

-B-A score of the Trail Making Test (TMT) according to normative data adjusted for age and education (Siciliano et al., 2019).

Secondary endpoints

• Total score on the Disability Rating Scale;
• System usability scale (SUS) for evaluating the Usability of VR in patients and professionals;
• modified Barthel Index (mBI) for functional disability. Exploratory endpoints T-otal score on the Italian version of the NeuroPsychiatric Inventory;
• Quantitative EEG;
• Blood biomarkers (BDNF, NFL, GFAP);
• Level of Cognitive Functioning;
• Total score on the Galveston Orientation and Amnesia Test;
• Scores on the Broken Hearts task (overall accuracy) and/or Trails task (baseline and shifting scores) on the Italian version of the Oxford Cognitive Screening.

Adverse Events Report: emptiness/disorientation, nausea/feeling of emptiness, headache, disorientation, dizziness, tremors/nausea/blurred vision/dizziness, nausea, vertigo and sense of unreality) will also be collected weekly in both groups from enrolment through termination of study protocol.

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20148
    • Recruiting
    • IRCCS Santa Maria Nascente Fondazione Don Gnocchi ONLUS
    • Contact: Angela Comanducci, PhD; Phone Number: 39 + 3493944645; Email: acomanducci@dongnocchi.it
  • Avellino
    • Sant'Angelo dei Lombardi, Avellino, Italy, 83054
      • Recruiting
      • Polo Specialistico Riabilitativo Fondazione Don Carlo Gnocchi ONLUS
      • Principal Investigator: Anna Estraneo, MD
      • Sub-Investigator: Alfonso Magliacano, PhD
      • Contact: Anna Estraneo, MD; Phone Number: +393396418648; Email: aestraneo@dongnocchi.it
  • Benevento
    • Telese Terme, Benevento, Italy, 82037
      • Recruiting
      • ICS Maugeri
      • Contact: Pasquale Moretta; Phone Number: 39 + 3315284938; Email: pasquale.moretta@icsmaugeri.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• LCF ≥4 at study entry;
• Age 18-75
• Stable clinical diagnosis (i.e., stable LCF);
• Time post-injury between 28 days and 6 months;
• Ability to complete the pre-test A section of the Italian version of the Trail Making Test (TMT);
• A pathological B-A score of the TMT according to normative data adjusted for age and education;
• Signed informed consent by the patient or by the patient's primary caregiver.

Exclusion Criteria:

• Severe medical conditions that might hamper participation in the rehabilitation sessions, or influence diagnosis;
• Previous neurodegenerative or acquired neurological diseases that affect cognitive domains (e.g., dementia)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Non-immersive VR-based training (VR); VR training focuses on enhancing executive processes but uses digital VR devices. During a VR session, the patient sits in front of the device and actively interacts with it, under the supervision of the therapist. The device contains many different exercises and for each of them the therapist can modify the virtual task scenario, increasing/decreasing its difficulty, creating a stimulating learning context in which the exercises are neither too easy nor too difficult. The exercises are divided into specific sub-domains, and include orientation, attentional processes, memory, and visual-executive functions.	Device: Khymeia®-Virtual Reality rehabilitation System (VRRS EVO SYSTEM or COMPACT VRRS ENGINE); fully immersive VR software created by clinicians and experts specialized in cognitive rehabilitation. Khymeia Devices are Medical Class 1 devices according to MDR. VRRS systems consist of a central process unit, complete with a capacitive touch screen LCD monitor.
Active Comparator: Traditional cognitive training (TCT); the standard treatment focused on executive processes and was based on a face-to-face approach between the therapist and the patient using paper and pencil tools and other traditional materials. The training of the executive abilities is carried out by working on categorization, planning, association processes, analogical reasoning, problem solving and coping strategies to simulate problematic situations, tailored on patients' deficits, in a protected context, thanks to interaction with the cognitive therapist according to a holistic-integrated approach.	Behavioral: Traditional cognitive training (TCT); face-to-face approach between the therapist and the patient using paper and pencil tools and other traditional materials. The training of the executive abilities is carried out by working on categorization, planning, association processes, analogical reasoning, problem solving and coping strategies to simulate problematic situations, tailored on patients' deficits

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trail Making Test (B-A score)	The TMT is a neuropsychological test assessing executive functions. Higher scores indicate a better performance	5 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
modified Barthel Index	It is a measure of functional disability, with higher scores indicating higher functional independence	5 weeks - 1 month after treatment
Disability Rating Scale	It is a measure of functional disability, with higher scores indicating higher disability	5 weeks - 1 month after treatment
System Usability Scale	It is a measure of usability and compliance. Higher scores indicate a better performance	5 weeks - 1 month after treatment
Trail Making Test (B-A score)	The TMT is a neuropsychological test assessing executive functions. Higher scores indicate a better performance	1 month after treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spectral metrics	Measure of quantitative EEG. Higher values indicate a better functional connectivity	5 weeks - 1 month after treatment
Microstate metrics	Measure of quantitative EEG. Higher values indicate a better functional connectivity	5 weeks - 1 month after treatment
Connectivity metrics	Measure of quantitative EEG. Higher values indicate a better functional connectivity	5 weeks - 1 month after treatment
Brain-derived neurotrophic factor	Blood biomarker. Higher value indicate higher brain plasticity	5 weeks - 1 month after treatment
Neurofilament-Light	Blood biomarker. Higher value indicate higher brain plasticity	5 weeks - 1 month after treatment
Glial fibrillary acidic protein	Blood biomarker. Higher value indicate higher brain plasticity	5 weeks - 1 month after treatment
NeuroPsychiatric Inventory	It is a measure of neurobehavioural and psychiatric disorders. Higher scores indicate a more severe disorder	5 weeks - 1 month after treatment
Level of Cognitive Functioning	A clinical scale assessing global cognitive functioning. Higher scores indicate a higher cognitive functioning	5 weeks - 1 month after treatment
Galveston Orientation and Amnesia Test	A clinical measure of post-traumatic amnesia. Higher scores indicate a more severe amnesia	5 weeks - 1 month after treatment
Oxford Cognitive Screening	A screening neuropsychological test assessing different cognitive domains. Higher scores indicate a better cognitive performance	5 weeks - 1 month after treatment

Collaborators and Investigators

• Sponsor: Anna Estraneo
• Collaborators: Istituti Clinici Scientifici Maugeri SpA; Ospedale Policlinico San Martino

Study record dates

Study Major Dates

• Study Start (Actual): October 28, 2024
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): November 30, 2026

Study Registration Dates

• First Submitted: June 14, 2024
• First Submitted That Met QC Criteria: June 19, 2024
• First Posted (Actual): June 26, 2024

Study Record Updates

• Last Update Posted (Estimated): September 29, 2025
• Last Update Submitted That Met QC Criteria: September 24, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: rehabilitation; virtual reality; executive functions; severe acquired brain injury
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries
• Other Study ID Numbers: VR-sABI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: A plan for wide dissemination of the results will be activated at the beginning, during and at the end of the project, through presentations at national and international conferences, and newsletters of scientific societies in the rehabilitation, neurological, and neuropsychological fields, to ensure that the results are shared with the scientific community. At the end of the project, the analysed results will be the subject of scientific publications in national and international peer-reviewed journals. The project will also be presented at regular conferences involving stakeholders (clinicians, patient and family associations) in accordance with the dissemination plan of the pnrr Fit4Med project.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No