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COMPUTER GAME-BASED REHABILITATION FOR POST-STROKE UPPER LIMB DEFICITS-SYSTEMATIC REVIEW AND META-ANALYSIS

Background: The need for intense rehabilitation protocols with easy applicability to improve for patient adherence and harness the potential neuroplasticity leading to improvement in the quality of life (QOL) in post-stroke patients. Several studies have described the benefits of virtual reality and video games in rehabilitation. Aims: To explore and determine if Computer game-based rehabilitation for post-stroke upper limb deficits after stroke is superior to conventional therapy in terms of (1) ICIDH based outcomes (2) Intervention duration (3) acceptability and adherence to the intervention. Methods: This systematic review and meta-analysis followed PRISMA guidelines. Several electronic databases were searched using specific keywords, to measure the effects of computer-game-based therapy in post-stroke patients compared to conventional therapy. Results: 14 studies were included after a systematic review, out of which 11 were included for analysis. Studies recording Wolf motor function test and box and block test have shown improvements with Computer-game-based therapy in addition to conventional therapy. No improvements were recorded in impairments and patient participation/Quality of life. CGBT was acceptable and reported no adverse effects. Conclusions: Computer-game-based therapy or non-immersive virtual rehabilitation is effective and acceptable for upper limb rehabilitation after stroke. With significant improvement in ‘activity-limitation,’ this mode of rehabilitation can be adapted for patient-specific needs. Its effects on impairment and quality of life need further exploration.


INTRODUCTION
The global burden of stroke is on the rise, recording 1.03 crore new strokes and 11.3 crore disability-adjusted life years (DALYs) per year [1]. Approximately 75% of deaths and more than 80% of DALYs occur as a response to stroke in low and middle-income countries (LMICs) [2,3]. Eighty percent of stroke survivors are limited by upper limb disability and only 5-20% show complete functional recovery [4,5]. There is no therapy protocol universally accepted for upper limb rehabilitation after stroke. Rehabilitation practices vary in duration, intensity, and frequency [6]. The intensity of rehabilitation and the rate of recovery post-stroke are directly proportional causing the poor outcome of death or deterioration to reduce [6,7]. Repetitive motor behavior during motor learning can aid to changes in representational organization in the motor cortex [8,9]. Animal (rats) models have suggested that after 2 weeks from the injury, the peri-infarct cortex starts responding to cortical afferents and consequently, limb responsiveness increases by stimulating those locations unrelated to limbs before a stroke. With an appropriate and adequately intense dosage of rehabilitation new connections are formed within cortical circuits (new dendritic spines, axonal connections stimulated by a molecular program on regeneration). Improvement in motor recovery induced by a brainderived neurotropic factor (BDNF) works by having direct effects on synapses, angiogenesis etc. post-stroke which can also be tapped through neuro-rehabilitation [10]. Studies suggest that therapy needs to be challenging, repetitive, task-specific, motivating and intensive for neuroplasticity to produce recovery [11,12].  have found a significant effect of augmented therapy on ADL (activities of daily living), especially when therapy begins at least 16 hours within the first six months after stroke [13]. The importance of repetition and intensity of rehabilitation is further described in a review and meta-analysis [14]. The NICE (National Institute for Health and Care Excellence) guidelines [15] and the National clinical guidelines for stroke in the United Kingdom and the Netherlands suggest a minimum of 45 minutes of therapy five times per week for optimal recovery over a period of time as needed by the patient. However, the actual duration of therapy provided is much less, ranging between 22-30 minutes per day [16][17][18]. One of the many interventions available for post-stroke upper limb rehabilitation is the widely researched CIMT (Constraint-induced movement therapy) and its modified versions. These are presently the best evidencebased physiotherapy approach causing significant neurophysiological changes in the brain and motor improvement with effects lasting at least up to 4-5 months. CIMT requires constraining the non-paretic upper limb for 60-90% of waking hours with 3-6 hours of task-specific therapy activities. (14) Such long duration of constraint leads to poor adherence and frustration in patients and their caregivers [19]. Many of the modified CIMT protocols lack transparency in reporting dosages and the barriers to implementation of such interventions need more exploration. Over the past decade, the use of Robotics, Virtual reality-based rehabilitation (VR) and Computer game-based therapy (CGBT) are supplementing and in some cases replacing conventional therapy approaches [20]. RATIONALE: The applicability of various therapy approaches and their factors that may enhance the use of the arms and hand in activities of daily living (ADL) require further investigation [4]. There is a need for intense rehabilitation protocols with easy applicability for patient adherence and to harness the potential neuroplasticity leading to improved quality-of-life (QOL) in patients poststroke. Several studies have described the benefits of virtual reality and video games in rehabilitation. The varying movement demands of computer games can be used in rehabilitation settings for tailor-made therapy protocols for stroke [21,22]. In this review and meta-analysis, we focus on the various CGBT used for rehabilitation of post-stroke upper limb impairments. For ease of understanding, we have differentiated between VR and CGBT. We have defined a CGBT as the use of non-immersive computer/video games in intervention while handling and manipulating real-life objects/remote for the tasks being performed (like Nintendo Wii (NW), XaviX, Sony Playstation MOVE etc.) and VR as the use of an immersive Virtual reality set up where a computer is used to generate stimuli to provide interaction opportunities with the environment, similar to real-world situations [23] and the patient interacts with the computer screen through motion and depth sensors, accelerometers, gyroscopes, robotic gloves etc. without grasping or manipulating real-life objects. Based on these differences, we have included only those therapies which used CGBT and excluded motion sensors, VR, and other therapies. Thus our objective is to explore and determine if Computer game-based rehabilitation after stroke is superior to conventional therapy in terms of (a) ICIDH based outcomes (b) Intervention duration (c) acceptability and adherence to the intervention. METHODS Search strategy and selection criteria (Figure 1) All sources of information were required to meet the following eligibility criteria: Inclusion criteria were Studies on CGBT after stroke for gross and fine motor movements of the upper extremity, Rehabilitation initiated not later than 6-month post-stroke, only randomized controlled trials were included, Articles published since January 2000 to August 2019. For Meta-analysis Studies recording Fugl-Meyer-assessment (FMA), Wolf-motor-function-test (WMFT), Box-and-block-test (BBT), Action-researcharm-test (ARAT) and Functional-independence-measure (FIM) scores were included. The exclusion criteria were Studies on post-stroke rehabilitation based on virtual reality, Studies reporting on robotic systems being applied in post-stroke rehabilitation, Studies written in languages other than English, Studies published before 2000. Exclusion criteria for Meta-analysis were studies that did not record standard deviations and those recording only the mean differences between and within the groups. We conducted this review and analysis based on PRISMA guidelines. We searched the following healthcare databases for articles of interest: PubMed, Medline, Embase, Isi Web of Science, ScienceDirect, SpringerLink, Google Scholar, ProQuest, EBSCO, Scopus, CINAHL Complete (i.e., EBSCO), and Cochrane Library (of Systematic Reviews). The systematic search was performed using keywords combined with Boolean operators: (stroke OR poststroke OR post-stroke OR cerebrovascular accident OR cerebrovascular disease OR apoplexy OR intracerebral hemorrhage OR intracerebral hemorrhage) AND (rehabilitation OR therapy OR treatment) AND (game OR computer game OR commercial game OR video game OR Nintendo Wii OR Wii OR Sony Playstation MOVE OR XaviX) AND (upper extremity OR upper limb OR arm OR hand).

Study selection
Two independent reviewers (DG, AS) evaluated the search results titles and abstracts to select potentially relevant articles. After that, the two authors (DG, AS) went through the full texts of the selected articles (except conference abstracts) to verify they fulfilled the inclusion criteria.

Data extraction
Studies were assessed and data collected for Type, intensity, and dosage of an intervention being applied, outcomebased on scales used in the studies [based on International Classification of Impairments, Disabilities (Activity Restrictions), and Handicaps (Participation Limitations), i.e., ICIDH] and Adherence and acceptability of the intervention by the patients and caregivers Methodological quality, risk of bias assessment PEDro checklist was used to assess the methodological quality while the risk of bias was measured using COCHRANE risk of bias tool. Publication bias was assessed according to funnel plots generated. For the meta-analysis section, all the data were summarised using Mean difference at 95% of a confidence interval. The studies provided 95% CI was transformed into SD, using a statistical formula. The medians and interquartile ranges converted into means and SDs using the appropriate formula [24]. The Log values were converted into original values using the antilog table.
The random-effect model was used to analyze the data if the studies were heterogeneous and fixed-effect models for homogeneous studies. The heterogeneity of the studies was calculated by using the Cochrane Q test and assessed by using I², which ranges from 0% to 100%. Analyses were conducted using Revman 5.3 by the Cochrane collaboration.

RESULTS
Out of the 14 studies included for this paper ( Table 1), 4 delivered NW exclusively to the intervention group, 7 delivered either NW/visual feedback exercises/exercises with smartphone tablet/arm support computerized training/hand orthosis in addition to routine care, 2 delivered mental practice/ transcranial direct current stimulation (tDCS) with NW and 1 used video games alone for the experimental group.

DISCUSSION
This review and meta-analysis are the first to describe the effects of CGBT (non-immersive-VR while handling and manipulating real-life objects/remote for the tasks being performed) on outcomes based on the ICIDH model. This study has contributed to the existing evidence of technological effects on rehabilitation in stroke rehabilitation in the following ways: (1) has included studies published since 2000, describing specifically the effects of CGBT (refer to introduction for our definition of CGBT).
(2) Found CGBT to be effective in improving activity-limitation but having insignificant effects on impairments and participation-restriction. We have not quantitatively analyzed the effects of duration and intensity of therapy provided; therapy initiated six months post-stroke on the outcomes measured. We have although given a brief and systematic description of these variables as qualitative findings based on the effect of intervention duration on the outcomes, acceptability of and adherence to CGBT and adverse effects if any. ( Table  2) 10 out of the 14 studies (71.43%) used NW gaming for intervention. The ease of availability and cost-effectiveness of such therapy modes can be exploited to provide effective interventions. 35.71% of the included studies provided intervention for 0.5 hours per session while the rest delivered one-hour sessions, some including the warm-up phase. Table 2: Qualitative findings

Intervention duration versus outcomes
The total time of rehabilitation therapy among the included studies varied from 8 hours to 31.5 hours. All studies reported improvements in clinical outcome scales after adjunctive CGBT. However, a study on the self administered homebased arm and hand rehabilitation argued the duration of therapy itself is the chief contributor to the upper limb motor improvements.
The majority of our studies concluded the CGBT to be as effective as conventional therapy (CT) and found no significant differences in functional outcomes. The symmetry of funnel plots shows low chances of publication bias but good methodological quality. Our meta-analysis revealed that studies reporting WMFT scores showed a significant improvement with therapy for 10-15 hours over 10days-5 weeks. The three studies considered were homogenous, with all of them using the NW game and 1 using additional trans-cranial direct current stimulation. The three studies, however, have varied sample sizes ranging from 10-71. The four studies reporting BBT were highly heterogeneous, with an intervention duration of 10-18 hours over ten days -6 weeks. Three of these studies used the NW game while 1 used additional passive hand orthosis for assistance. These findings from our meta-analysis suggest the positive effects of CGBT in improving activity-limitation. Larger RCTs using such interventions with varying durations in the various phases after stroke need to be explored. The impairment and participation-restriction categories did not show promising results, although these can partly be attributed to various reasons like heterogeneity in studies, small sample sizes etc.

Limitations:
Our study included only those studies where stroke had occurred a maximum of 6 months before intervention delivery with limited long-term follow-up. There was significant heterogeneity between studies reporting FMA and BBT. Our analysis was based on outcome measures and not on the duration of intervention or the phase poststroke. These factors may limit the implications of our findings.

CONCLUSIONS
Computer-game-based therapy or non-immersive rehabilitation is effective and acceptable for rehabilitation after stroke. With significant improvement in 'activitylimitation, ' this mode of rehabilitation can be adapted for patient-specific needs. Its effects on impairment and quality of life need further exploration.