Clinical trial NCT05163210: Effectiveness of AOT Based on Virtual Reality in Stroke Rehabilitation.
Official title: Effectiveness of Action Observation Therapy Based on Virtual Reality Technology in Motor Rehabilitation of Paretic Stroke Patients: a Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Stroke
Hemiplegia
Hemiparesis
Keywords: action observation therapy
mirror neuron system
stroke
virtual reality
motor learning
Lead sponsor: Azienda Ospedaliero-Universitaria di Parma
Sponsor class: OTHER
Collaborators: name: Ministry of Health, Italy
First posted: 2021-12-20
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study will consist in a multicentric, randomized, allocation concealed (waitlist-controlled) and evaluator-blinded clinical trial (RCT) with two investigative arms, using an intensive rehabilitation program based on the combined use of AO followed by imitation in VR (AO+VR) (experimental intervention) compared to a control treatment based on observation of control videos followed by action execution in VR (CO+VR) (control intervention).
Primary purpose: TREATMENT

Brief summary: Rehabilitation of paretic stroke patients, aimed to improve function of the impaired upper limb, uses a wide range of intervention programs. A new rehabilitative approach, called Action Observation Therapy (AOT), based on the discovery of mirror neurons, has been used to improve motor functions of adult stroke patients and children with cerebral palsy. Recently, Virtual Reality (VR) provided the potential to increase the frequency and the effectiveness of rehabilitation treatment and offered challenging and motivating tasks. The purpose of the present project is to design a randomized, controlled, six-month follow-up trial (RCT) for evaluating whether action observation (AO) added to standard VR (AO+VR) is effective in improving upper limb function in patients with stroke, compared with a control treatment consisting in observation of naturalistic scenes (CO) devoid of action content, followed by VR training (CO+VR). The AO+VR treatment may represent an extension of the current rehabilitative interventions available for recovery after stroke and the outcome of the project could allow to include this treatment within the standard sensorimotor training or in individualized tele-rehabilitation.

Detailed description: Stroke is the leading cause of disability among adults, and more than 60% of stroke survivors have motor deficits, particularly related to the upper limb. Stroke rehabilitation usually involves intensive motor training aimed to promote adaptive plasticity, by reducing motor deficits and developing new motor learning strategies. It has recently been proposed that the systematic use of action observation (AO) followed by imitation (Action Observation Therapy - AOT) is an effective way to improve motor functions and to promote upper limb recovery in patients with motor disorders. During a typical AOT session, a series of daily life actions (e.g., grasping a key and inserting it into a lock) are practiced for about 2/5 weeks (with a frequency of 3-5 daily sessions per week). During each rehabilitation session, patients are instructed by the therapist to observe a specific action performed by an actor, presented as a short video-clip on a monitor, and afterwards to reproduce the previously observed action with the paretic limb. In each video, a single motor act is usually presented as observed from different perspectives (e.g., subjective, front or side view). This therapy is based on the neural model of the Mirror Neuron System (MNS), originally discovered in the monkey premotor and parietal cortex, formed by visuomotor neurons that become active both when a monkey performs a goal-directed motor act and when it simply observes the same o a similar motor act performed by the experimenter. A comparable MNS has also been identified in humans using different electrophysiological and neuroimaging techniques. In humans, the two main nodes of the MNS are the inferior parietal lobule (IPL) and the ventral premotor cortex (PMv), plus the caudal part of the inferior frontal gyrus (IFG).

AOT is considered particularly useful for activating the motor system in those conditions in which intensive motor training is not feasible, because of the severity of the impairment of motor functions or due to the presence of pain, inflammation, muscle fatigue. In the last years, new Virtual Reality-based (VR) rehabilitation treatments have been introduced, in order to present rehabilitation exercises in more practical and friendly setting. These treatments are generally well accepted by the patients because they offer several advantages: relatively low cost (in particular for semi-immersive versions), engaging environment, real-time personalization of exercises and greater adaptability to the patient's clinical features and progress, as well as possibility to record motor performance and to acquire and provide feedback to the patient in real time. Furthermore, VR exercises usually require a minimal therapist supervision, thereby facilitating home-based form of rehabilitation.

Several studies support the application of VR methods in the rehabilitation of the hemiplegic upper limb in patients with stroke. Recent literature reviews provided evidence for improvement of upper limb motor function and daily life activity after VR-based training, as compared to vicarious standard interventions. However, clinical evidence based on rigorous RCT on the effect of combined use of observation of actions followed by their immediate imitation in a VR environment (AO+VR therapy) are lacking, especially in the case of rehabilitation applied during the chronic phase after the stroke.

The main hypothesis is that, for the recovery of motor function of hemiplegic stroke patients, the combined rehabilitation treatment (AO+VR therapy) is more effective than a control treatment (Control Observation - CO) based on observation of videos without motor content (e.g., environmental natural scenes ), followed by the execution of actions in VR (CO+VR control therapy),.

In sum, the planned trial will examine the following hypotheses:

1. AO+VR is an effective tool to promote upper limb control in paretic stroke patients, and its effects are higher than CO+VR control treatment.
2. motor performance, cognitive level, and structural brain damage assessed before treatment are correlated to the degree of improvement determined by the AO+VR intervention;
3. AO+VR intervention determines, as compared to CO+VR control treatment, plastic functional changes of the MNS activity.

Eligibility criteria: Inclusion Criteria:

1. primarily motor symptoms with unilateral upper limb paresis (controlled via standard neurological examination);
2. residual movement ability of the paretic upper limb, controlled by Medical Research Council (MRC) index \> 2 and \< 4, active use of the hemiplegic limb, from minimal (mainly for assistance tasks to the preserved limb) to discrete (characterized by coarse manipulation and an inability to perform precision grip);
3. sufficient cooperation and cognitive understanding to participate in the activities, controlled by the investigator recruiting the patient.

Exclusion Criteria:

1. severe cognitive impairment (score \<20 on MMSE);
2. presence of severe forms of unilateral spatial neglect (Bells Test, cut-off =/\> 50% ).
3. presence of severe anosognosia;
4. presence of severe language comprehension deficits assessed by clinical examination;
5. presence of severe untreated psychiatric disorders;
6. sensory impairment hindering participation and/or not compensated visual deficits of central origin;
7. drug-resistant epilepsy;
8. presence of cognitive disability (IQ \< 65) controlled by administration of Wechsler Adult Intelligence Scale IV (WAIS-IV) (Wechsler, 2008).

Primary outcomes:
measure: Change in Box and Block test (BBT) score between three time points
timeFrame: Baseline (T0), after 5 weeks of treatment (T1) and after 6 months (T2).
Secondary outcomes:
measure: Change in Modified Ashworth scale (MAS) score between three time points
timeFrame: Baseline (T0), after 5 weeks of treatment (T1) and after 6 months (T2).
measure: Change in Motricity Index (MI) score between three time points
timeFrame: Baseline (T0), after 5 weeks of treatment (T1) and after 6 months (T2).
measure: Change in Rankin Scale (RS) score between three time points
timeFrame: Baseline (T0), after 5 weeks of treatment (T1) and after 6 months (T2).
measure: Change in Barthel Index (BI) score between three time points
timeFrame: Baseline (T0), after 5 weeks of treatment (T1) and after 6 months (T2).
Other outcomes:
measure: Change of functional Magnetic Resonance Imaging (fMRI) brain activation between two time points
timeFrame: Baseline (T0) and after 5 weeks of treatment (T1).
Locations:
city: Parma
country: Italy
facility: Centro Cardinal Ferrari, Gruppo S. Stefano Riabilitazione
state: Emilia-Romagna
city: Bergamo
country: Italy
facility: Istituto Clinico Quarenghi
state: Lombardia
Study officials:
affiliation: Azienda Ospedaliero-Universitaria di Parma
name: Antonino Errante, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Buchignani B, Beani E, Pomeroy V, Iacono O, Sicola E, Perazza S, Bieber E, Feys H, Klingels K, Cioni G, Sgandurra G. Action observation training for rehabilitation in brain injuries: a systematic review and meta-analysis. BMC Neurol. 2019 Dec 27;19(1):344. doi: 10.1186/s12883-019-1533-x.
citation: Ertelt D, Small S, Solodkin A, Dettmers C, McNamara A, Binkofski F, Buccino G. Action observation has a positive impact on rehabilitation of motor deficits after stroke. Neuroimage. 2007;36 Suppl 2:T164-73. doi: 10.1016/j.neuroimage.2007.03.043. Epub 2007 Mar 31.
citation: Rizzolatti G, Cattaneo L, Fabbri-Destro M, Rozzi S. Cortical mechanisms underlying the organization of goal-directed actions and mirror neuron-based action understanding. Physiol Rev. 2014 Apr;94(2):655-706. doi: 10.1152/physrev.00009.2013.
citation: Laver KE, Lange B, George S, Deutsch JE, Saposnik G, Crotty M. Virtual reality for stroke rehabilitation. Cochrane Database Syst Rev. 2017 Nov 20;11(11):CD008349. doi: 10.1002/14651858.CD008349.pub4.
citation: Errante A, Saviola D, Cantoni M, Iannuzzelli K, Ziccarelli S, Togni F, Simonini M, Malchiodi C, Bertoni D, Inzaghi MG, Bozzetti F, Menozzi R, Quarenghi A, Quarenghi P, Bosone D, Fogassi L, Salvi GP, De Tanti A. Effectiveness of action observation therapy based on virtual reality technology in the motor rehabilitation of paretic stroke patients: a randomized clinical trial. BMC Neurol. 2022 Mar 22;22(1):109. doi: 10.1186/s12883-022-02640-2.