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USE OF VIRTUAL REALITY-BASED TRAINING IN DIFFERENT FIELDS OF REHABILITATION: A SYSTEMATIC REVIEW AND META-ANALYSIS

Sebastian RUTKOWSKI, PhD1, Pawel KIPER, PhD2*, Luisa CACCIANTE, MSc3, Błażej CIEŚLIK, PhD4, Justyna MAZUREK, PhD5, Andrea TUROLLA, PhD3 and Joanna SZCZEPAŃSKA-GIERACHA, PhD6 From the 1Department of Physical Education and Physiotherapy, Opole University of Technology, Opole, Poland, 2Azienda ULSS 3 Serenissima, Physical Medicine and Rehabilitation unit, Venice, Italy, 3Laboratory of Neurorehabilitation Technologies, San Camillo IRCCS s.r.l., Venice, Italy, 4Institute of Physical Education, Tourism and Physiotherapy, Faculty of Pedagogy, Jan Długosz University, Czestochowa, Poland, 5Department and Division of Medical Rehabilitation, Wroclaw Medical University, Wroclaw, Poland, 6Department of Physiotherapy, University School of Physical Education, Wroclaw, Poland


Assessment of risk of bias in included studies
Risk of bias for the included studies was assessed independently by 2 reviewers, who were supported by a third researcher in case of disagreement. Assessment was conducted following the criteria set out by the Cochrane Collaboration in the Cochrane Handbook for Systematic Reviews of Interventions (14). The following domains were evaluated: (i) selection bias: sequence generation, allocation concealment; (ii) detection bias: blinding of outcome assessment; (iii) attrition bias: incomplete outcome data; and (iv) reporting bias: selective reporting. It was decided to omit the domain that assesses the blinding of participants, as blinding is not possible in most cases and because it was deemed that this domain related to the nature of the intervention, instead of to study quality, as Laver et al. already stated (15). Risk of bias for each domain was coded as "high risk", in case of a high possibility in the occurrence of bias; "low risk", in case of a low possibility of bias; and "unclear risk", when the real incidence of bias could not be defined exactly.

Statistical analysis
A review was conducted using Review Manager 5.3 (RevMan) for statistical analysis. The methodological quality of studies was recorded in the risk of bias tables. Outcome measures were assigned to each domain assessed (upper limb function, hand dexterity, balance and gait) for both specialized and gaming systems. Treatment effect was evaluated using mean difference (MD) in case of homogeneous outcome measures, or standardized mean difference (SMD) when the outcomes were assessed with different scales, and 95% confidence intervals (95% CI) were calculated. A meta-analysis was carried out based on a randomeffects model or fixed effect model with 95% CIs.
Heterogeneity was assessed considering intervention and outcome measures, pooling data for the most clinically homogeneous trials. Statistical heterogeneity was assessed with the I² statistic, establishing the cut-off value as 50%.
Analysis of subgroups was planned in relation to the different types of rehabilitation (e.g. neurorehabilitation, paediatric rehabilitation) and according to the different aetiologies of motor impairments (i.e. stroke and tetraplegia)

RESULTS
Electronic searching of the PubMed database identified 481 records (Fig. 1). After screening the abstracts, 27 papers were selected for full-text reading. Of these, a final total of 20 papers were included in the review. Of the 20 included studies, 16 (with 518 participants) related to treatment of neurological disorders, 1 (with 30 participants) related to treatment of orthopaedic impairment, 1 (with 70 participants) related to geriatric patients, and 2 (with 128 participants) related to treatment of paediatric patients. Table I shows the characteristics of the included studies. Fig. 2 shows the risk of bias in the included trials.

Summary of included studies
All studies focused on VR treatment for the upper or low er limb. Within the neurological diseases 14 studies assessed the effects of VR treatment in patients after used in recovery from neurological disease (5), and in paediatrics (e.g. cerebral palsy) (6,7), orthopaedics, (8) and psychiatry (e.g. for phobia treatment) (9). In the last decade, VR has also been used successfully in telemedicine and telerehabilitation, opening up a new mode of health delivery (10). Furthermore, a wide range of VR systems are available, which can be used for treatment both in clinical and home-based environment. These are grouped as socalled "specialized" VR (i.e. specifically developed therapeutic VR systems) and gaming VR (i.e. commercial VR-game consoles that can be used in clinical practice) (5,11,12).

Objectives
The objectives of this systematic review were to analyse the effectiveness of VR-based interventions within several fields of rehabilitation, and to investigate whether the outcomes of VR-based interventions differ, in their effects on upper or lower limb function, gait and balance, with respect to the type of VR system used.

MATERIAL AND METHODS
This systematic review was performed according to the Pre ferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting systematic reviews (13).

Search strategy
Studies related to VR training were considered eligible for review. PubMed database was searched for appropriate articles, using the following criteria: ( ). Articles were filtered by date of pub lication, with the aim of including only those published within the last 7 years, due to the large available literature on the topic of VR. Only randomized controlled trials (RCTs) were included. All treatments provided to participants were reported with as much detail as possible. If needed, the trials' author was contacted for clarification and to obtain missing data. stroke for both upper and lower limb impairment (12,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). The following studies focused on upper limb recovery (12, 17-19, 21, 23, 25-28 (1) Chronic post stroke+VR (2) Chronic post-stroke control group (1) 9 (2) 7 The OT was delivered for 20 minutes by trained occupational therapists who were blinded to the protocol in order to provide participants the same OT used in the conventional clinical setting.   (26). They concluded that game-based VR canoe paddling training is an effective rehabilitation therapy that enhances postural balance and upper extremity function in patients with subacute stroke when compared with the control group (p < 0.05).
One study evaluated upper and lower limb developmental coordination disorder in children (11). The authors showed that the Movement Assessment Battery for Children test (p < 0.0001), the Bruininks Oseretsky test (p < 0.0001) and Functional Strength Measure (p < 0.0001) changed significantly within groups. However, they concluded that skills acquired within VR-game scenarios did not necessarily transfer into the real world (11). One study evaluated VR treatment in relation to cerebral palsy, showing a statistically significant difference between groups in muscular strength flexion and extension (p < 0.05), in the Pediatric Balance Scale (p < 0.01), 10-m walking test (p < 0.001) and 2-min walking test (p < 0.001). The authors suggest that VR treadmill training is effective for gait and balance improvement (6). One study involved patients affected by multiple sclerosis. Both groups showed a main effect of time on the centre of pressure (CoP) path length with eyes open (p < 0.024), sway rate with eyes open (p < 0.035), Functional Reach Test (p < 0.001), Four Square Step Test (p < 0.031) and the Fear of Falls self-reported questionnaire (p < 0.023) (29). One study assessed effects of VR therapy on upper limb impairment in patients with spinal cord injury (SCI). Both groups demonstrated clinical, but no significant, changes related to arm function. Moreover, all patients from the experimental group showed high levels of satisfaction with the VR system (28). Within orthopaedics only one study was included, which assessed the effects of VR therapy in recovery of subacromial impingement syndrome. The authors demonstrated that intensity of pain can be reduced with VR training (p < 0.05) (8). One study evaluated the effect of VR on lower limb in geriatric patients, showing improvement in balance disorders and fall prevention (p < 0.01) (30).

Random sequence generation (selection bias).
Thirteen studies were assessed as having a low risk of bias for this domain, as the authors described a random component in the sequence-generation process. Five studies did not report information about the randomization process, resulting in an unclear risk of bias. The remaining studies were assessed as having a high risk of bias, with inappropriate randomization methods used.

Allocation concealment (selection bias).
Thirteen studies were assessed as having a low risk of bias in this domain, as the allocation methods used were appropriate. Six studies did not report information about the allocation method used, and one study presented a high risk of bias, as therapists were not blinded to the patients' assignment.

Blinding of outcome assessment (detection bias).
Seventeen studies were at low risk of bias, as outcome measures were assessed by therapists who differed from those who provided treatment sessions. Two studies did not state whether assessors were blinded, hence the risk of bias was unclear. One study was judged to be at high risk of bias, as evaluations and treatment programmes were both carried out by the same therapist.

Incomplete outcome data (attrition bias).
Sixteen studies were at low risk of bias, as most of the participants were included in the final analysis. Four studies reported a high risk of bias due to the large number of drop outs.
Selective reporting (reporting bias). All studies reported all the prespecified outcomes. Only the study of Zondervan et al. (17) did not publish all outcome measures registered in the study protocol, resulting in a high risk of bias for this domain.

Comparison of conventional treatment vs specialized virtual reality
Upper limb function (all measures). A total of 8 studies, with an overall total of 204 participants, who were divided into subgroup analysis with regard to aetiology, were analysed (i.e. 7 studies with post-stroke patients and one study with patients after SCI. The meta-analysis did not provide significant evidence that specialized VR is superior to conventional treatment. However, it should also be noted that the analysis was influenced by high heterogeneity. The analyses were performed using standardized mean difference (SMD) with random effects model, since 6 studies used the Fugl-Meyer upper extremity scale, one used the Wolf Motor Function test and one used the Motricity Index. No significant differences were found between specialized VR and conventional treatment in stroke patients (SMD 0.80; 95% CI -0.19 to 1.80, I 2 = 88%) in SCI patients (SMD -0.13; 95% CI -0.83 to 0.58), or in total comparison (SMD 0.68; 95% CI -0.18 to 1.54, I 2 = 87%) (Fig. 3).

Upper limb function (Fugl Meyer).
A total of 5 studies, with an overall total of 138 stroke survivors, were analysed in relation to upper limb function measured with the Fugl Meyer test. Mean difference (MD) with a fixed effect model was used for analysis. Significant differences (MD 8.41; 95% CI 7.13 to 9.68, I 2 = 46%) were observed between specialized VR and conventional treatment (Fig. 4).

Upper limb hand dexterity function (all measures).
Five studies, with an overall total of 110 post-stroke patients, were analysed in relation to upper limb hand   dexterity. SMD with random effects model was used for analyses, since 1 study used the Chedoke Arm and Hand Activity Inventory, 2 used the Fugl Meyer upper extremity hand section, and 2 used the Nine Hole Peg Test. No significant differences were found between specialized VR and conventional treatment (SMD 0.98; 95% CI -0.51 to 2.47, I 2 = 91%) (Fig. 5).
Lower limb function (gait). For gait, 3 studies, with an overall total of 106 post-stroke patients, were analysed. SMD with a fixed effect model was used for analyses, since 2 studies used a Timed Up and Go test, and one used temporal gait speed parameter. No significant differences were found between specialized VR and conventional treatment (SMD -0.36; 95% CI -0.74 to 0.03, I 2 = 0%) (Fig. 6).

Lower limb function (balance).
For balance, 2 studies, with an overall total of 55 patients, were analysed. Mean difference (MD) with a fixed effect model was used for analyses. Significant differences (MD 3.07; 95% CI 1.11-5.03, I 2 = 0%) were observed between specialized VR and conventional treatment (Fig. 7).

Comparison of conventional treatment vs gaming virtual reality Upper limb function (all measures).
For upper limb function, 2 studies, with an overall total of 171 participants, were analysed. The analysis was performed using SMD with random effects model, one study used Manual Function test and one used Wolf Motor Function. Significant differences (SMD 0.34; 95% CI    www.medicaljournals.se/jrm 0.04-0.64, I 2 = 0%) were observed between gaming VR and conventional treatment (Fig. 8).

Upper limb hand dexterity function (all measures).
For upper limb dexterity function, 2 studies, with an overall total of 171 participants, were analysed. For hand dexterity function, SMD with a fixed effect model was used for analyses, since one study used Manual Function test hand section and one used Box and Block Test. No significant differences were observed between gaming VR and conventional treatment (SMD -0.12; 95% CI -0.42 to 0.18, I 2 = 74%) (Fig. 9).
Lower limb function (gait). For lower limb function, 8 studies, with an overall total of 63 participants, were analysed, with subgroup analysis in relation to aetiology (i.e. one study with post-stroke patients and one study with cerebral palsy (CP) patients). SMD with a fixed effect model was used for analyses, since 2 studies used the Timed Up and Go test and one used a 10m walk test. No significant differences were noted between gaming VR and conventional treatment in post-stroke patients (SMD -0.03; 95% CI -0.62 to 0.56, I 2 = 25%), CP patients (SMD 0.60; 95% CI -0.35 to 1.55) or in total comparison (SMD 0.15; 95% CI -0.36 to 0.65, I 2 = 22%) (Fig. 10).
Lower limb function (balance). For balance, SMD with random effects model was used for analyses, since 2 studies used the Berg Balance Scale and one used the Pediatric Balance Scale. No significant differences were noted between gaming VR and conventional treatment in post-stroke patients (SMD 0.41; 95% CI -0.75 to 1.57, I 2 = 73%), CP patients (SMD 0.29; 95% CI -0.64 to 1.22) or in total comparison (SMD 0.37; 95% CI -0.32 to 1.06, I 2 = 46%) (Fig. 11).  function, conversely less than 25% are unable to walk without full physical assistance (33,34). Another reason can be related to patient safety during gait or balance treatment, which requires specialized VR systems.
It was observed that the specialized VR systems were used both for treatment and assessment of patients. This was especially common in the neurological field, prob ably due to the fact that neurological patients require specific and individual training programmes, and only a directed in clinical settings system can be beneficial for these kind of patients. On the other hand, gaming systems were used with children, which can be advantageous because some boring or repetitive exercises can be substituted by more interactive activities. This may help both clinicians and parents to motivate children effectively to comply with their daily therapy.
VR is a growing technology that can provide an important addition to traditional rehabilitation modalities. Research shows that most disabled patients experience not only physical disorders, but also mental health problems (e.g. depression or cognitive impairment) (35,36). Thus, it could be interesting to combine different motor training aspects with psychological and cognitive ones (e.g. mood improvement, strengthened motivation to active engagement in rehabilitation process, visual-spatial orientation and cognitive stimulation). Future studies should consider this translational aspect for VR therapy.

Study limitations
This study has some limitations that need to be addressed. Firstly, only one database was searched for studies, due to the wide number of publications related to the rehabilitation field. Secondly, only full free text articles were included, providing an overview of accessible clinical outcomes for a wide audience. In addition, no information was obtained from authors related to p-values for the results of included studies.

Implications for clinical practice
Rehabilitation based on VR therapy is emerging as an effective modality for the treatment of balance as well as the upper extremity. VR-based therapy is widely used in the neurological field, especially for rehabilitation after stroke. To date, studies have shown some efficacy of VR-based approach with both specialized and gaming VR systems for gait and hand dexterity; however, this was not significant. Future research into the use of VR in neurological patients should utilize larger samples assessed over time, in order to investigate long-term effects and psychological aspects of the therapeutic intervention. Specialized VR and gaming VR can be advantageous for

DISCUSSION
VR therapy has been shown to result in improvements in analysed parameters, but not with statistical significance for all conditions in comparison with conventional treatment. Significant differences were observed between specialized VR and conventional treatment for upper limb function (Fugl Meyer) and lower limb function (balance). Comparative analysis of conventional treatment vs gaming VR, found significant differences only within upper limb function (all measures).
This review shows that most recipients of VR therapy are patients with neurological disorders, mainly stroke. All studies of patients after stroke showed improvement after VR therapy in comparison with conventional therapy in both upper and lower limbs (11,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). The results of the studies included in this review reveal that stroke patients benefit from this innovative treatment, probably through enhanced stimulation provided by an artificially generated environment leading to the activation of motor learning processes. According to the motor learning paradigms, the efficient movement should be repeated, emulating a reference model as exactly as possible, with the aim of achieving the best motor performance (32). Thus, motor learning paradigms can be seen as a basis for movement re-learning and, according to the results of analysed studies, the VR environment has the potential to stimulate both supervised and reinforcement learning, bas ed on augmented visual, acoustic and sensitive feedback.
VR therapy was also used to treat people with developmental coordination disorder and cerebral palsy, showing improvement in learning new movements from VR environments. VR therapy was also shown to be effective for treating people with multiple sclerosis and SCI. These findings demonstrate a wide range of applications for VR in rehabilitation interventions, and its possible advantage in different clinical settings. In addition, studies included in this review did not find any contraindications to the use of this form of therapy. Only one study was published within the orthopaedic field, in which authors evaluated the effect of a VR programme for recovery of subacromial impingement syndrome (SAIS), showing that the VR training was more effective than home exercise programmes in the short-term in subjects with SAIS (8).
Most of the included studies focused on upper limb treatment, whereas training for the lower limb concentrated mostly on balance. This difference may be due to the complexity of treating upper limb function after stroke, relying on changes in muscle synergies of the upper extremity leading to stereotyped voluntary movements. This change is related to both disrupted motor pathways and altered neural reorganization especially following a stroke. Importantly, approximately 60% of stroke survivors do not recover their upper limb www.medicaljournals.se/jrm the upper extremity, but not for balance treatment. There is insufficient evidence across free available articles to reach conclusions about the effects of specialized VR and gaming VR on hand dexterity and gait speed.

Implications for further research
This systematic review highlights the need for further research into VR-based approaches for rehabilitation interventions for gait and hand dexterity. Furthermore, due to the differences in outcome measures, in order to better compare data from different trials specific protocols with equal outcome measures should be developed. Finally, improvements in the methodological quality of evidence are needed, by increasing the number of participants in trials, and correctly randomizing them, in order to minimize the possible effects of confounding factors.

Low risk
All expected and prespecified outcomes were reported Cho et al., 2015 (20) Bias Authors' judgement Support for judgement

Random sequence generation (selection bias)
Low risk

Sealed envelopes
Blinding of outcome assessment (detection bias)

Low risk
Outcome assessor blinded Incomplete outcome data (attrition bias)

Low risk
One participant from intervention group and one participant from control group were lost to follow-up. Losses unlikely to affect final results Selective reporting (reporting bias)

Low risk
All prespecified outcomes reported Cho et al., 2016 (6) Bias Authors' judgement Support for judgement Random sequence generation (selection bias)

Unclear risk
Participants were randomly allocated by lots Allocation concealment (selection bias)

Low risk
Participants were allocated by lots Blinding of outcome assessment (detection bias)

Low risk
The two evaluators were blinded to the group allocation of the participants Incomplete outcome data (attrition bias)

Low risk
All participants included in the analysis Selective reporting (reporting bias)

Bias
Authors' judgement Support for judgement

Random sequence generation (selection bias)
Low risk

Sealed envelopes
Blinding of outcome assessment (detection bias)

Low risk
Outcome assessor blinded Incomplete outcome data (attrition bias)

High risk
Nine participants lost to follow-up, reasons for losses were disclosed. Losses likely to influence final results Selective reporting (reporting bias)

Low risk
All prespecified outcomes reported www.medicaljournals.se/jrm