TYPE Original Research

PUBLISHED 15 July 2022

DOI 10.3389/fpsyt.2022.952828

Effects of a virtual reality serious

OPEN ACCESS game training program on the
EDITED BY
Kelly Anne Allott,
The University of Melbourne, Australia
cognitive function of people
REVIEWED BY
Roos Pot-Kolder,
diagnosed with schizophrenia: A
The University of Melbourne, Australia
Caroline Gao,
The University of Melbourne, Australia
randomized controlled
*CORRESPONDENCE
Jianying Yu trial
314504913@qq.com

SPECIALTY SECTION Xu Wang1,2 , Xiaomin Kou1 , Xiandong Meng1 and Jianying Yu1*
This article was submitted to
1
Schizophrenia, West China Hospital, Sichuan University, Chengdu, China, 2 West China School of Nursing, Sichuan
a section of the journal University, Chengdu, China
Frontiers in Psychiatry

RECEIVED 25 May 2022

ACCEPTED 28 June 2022
PUBLISHED 15 July 2022
Background: Cognitive impairment persists through the course of
CITATION
schizophrenia and affects patients’ activities of daily living.
Wang X, Kou X, Meng X and Yu J
(2022) Effects of a virtual reality serious
Aim: This study aims to investigate the effects of a virtual reality (VR)
game training program on
the cognitive function of people serious game training program on the cognitive function of people diagnosed
diagnosed with schizophrenia: with schizophrenia.
A randomized controlled trial.
Front. Psychiatry 13:952828. Materials and Methods: Sixty-four eligible people diagnosed with
doi: 10.3389/fpsyt.2022.952828
schizophrenia were recruited and randomly assigned to the intervention
COPYRIGHT
© 2022 Wang, Kou, Meng and Yu. This
group (n = 31) and the control group (n = 33). The control group received
is an open-access article distributed standard psychiatric care. The intervention group was trained with an
under the terms of the Creative
additional VR game twice a day for at least 10 days during hospitalization.
Commons Attribution License (CC BY).
The use, distribution or reproduction in Cognitive function was measured at enrollment and before discharge using
other forums is permitted, provided the Brief Cognitive Assessment Tool for Schizophrenia.
the original author(s) and the copyright
owner(s) are credited and that the Results: Compared with those of the control group, the results of the working
original publication in this journal is
cited, in accordance with accepted memory (t = 3.463, Cohen’s d = 0.87, p = 0.001) and executive function (TMTA:
academic practice. No use, distribution Z = -2.272, Cohen’s d = 0.59, p = 0.023; TMTB:Z = -2.365, Cohen’s d = 0.62,
or reproduction is permitted which
does not comply with these terms. p = 0.018) of the intervention group after intervention were significantly better.
However, there was no significant difference in the results of social cognition
(Z = -1.394, Cohen’s d = 0.35, p = 0.163) between the two groups.
Conclusion: Intensive active virtual reality serious game training in addition
to standard psychiatric care can significantly improve working memory and
executive function in people diagnosed with schizophrenia.
Implications for Practice: When helping improve the cognitive function of
people diagnosed with schizophrenia, mental health professionals should
identify cognitive domains to be enhanced and develop corresponding
serious game training strategies.
KEYWORDS

schizophrenia, virtual reality, serious game, cognitive function, randomized

controlled trial

Frontiers in Psychiatry 01 frontiersin.org

Wang et al. 10.3389/fpsyt.2022.952828

Introduction by poor study methods. Of those, cognitive training programs

involving teaching strategies used in the tasks or combined
Schizophrenia is a complex serious mental disorder and one with psychiatric rehabilitation had a much larger effect. Another
of the top 10 disabling diseases, affecting 21 million people in intervention with a positive cognitive outcome was physical
the world (1). It is usually noticed and diagnosed by positive exercise. A recent meta-analysis demonstrated that aerobic
symptoms, in particular delusions and hallucinations (2). exercise significantly improved the global cognition of people
Negative symptoms, such as diminished emotional expression, diagnosed with schizophrenia (17).
anhedonia and asociality, have also been included in the Despite the encouraging results of non-pharmacological
diagnostic criteria of schizophrenia as one of the five core interventions, one common problem that hinders cognitive
dimensions in the Diagnostic and Statistical Manual of Mental function recovery is participant’s low involvement or high
Disorders 5th edition (DSM-5) (3). In recent years, some dropout rate. Affected by negative symptoms of schizophrenia
psychiatrists have proposed that focusing solely on psychotic and the sedative effect of antipsychotics, people diagnosed with
symptoms of schizophrenia may be a conceptual fallacy and schizophrenia are less motivated to participate in treatments
hampers progress in understanding and treating the disorder and more likely to drop out of treatments halfway. To
(4, 5). maintain and increase participant’s involvement, interventions
Schizophrenia is associated with impairment across a need to be interesting and attractive. Serious games can
wide range of higher-order cognitive performance domains fulfill this requirement. Serious games are mental contests
(6). Cognitive impairment has been detected even before designed to mimic specific activities that utilize entertainment
the apparent onset of schizophrenia, persists throughout the to educate or train people in a virtual environment (18).
course of the disease and is further aggravated during acute What differentiates serious games from entertainment games
episodes (7). Approximately 75 to 80% of people diagnosed is that their development requires the formulation of rules
with schizophrenia have cognitive impairment, including a and techniques based on certain therapeutic theories. For
decline in attention test, processing speed, visual and verbal example, guided by cognitive load theory, a titrated increase
learning, working memory and executive function, which makes in difficulty helps participants maintain focus during the game
it difficult for patients to accurately perceive, process, and (19); in order to change biased perceptions of social interaction,
remember information (8). Consequently, people’s ability to the techniques of cognitive behavioral therapy need to be
study, work or manage daily affairs is impaired, which in turn incorporated into gameplay (20). There has been a growing
leads to reduced social function (9). Studies have suggested that, amount of research using serious games to amplify learning
compared with psychotic symptoms, cognitive function is more and motivation in the therapeutic prevention and treatment of
strongly correlated with and predictive of functional outcomes patients with various medical conditions (21, 22).
of people diagnosed with schizophrenia (10, 11). Therefore, To remediate the cognitive function of people diagnosed
maintaining or even enhancing cognitive function is of great with schizophrenia, we developed a virtual reality serious
significance in improving the prognosis of people diagnosed game based on the theory of neuroplasticity, which advocated
with schizophrenia. that the brain nervous system can constantly adjust the
However, the results of interventions for cognitive connection between nerves under the stimulation of the
impairment in people diagnosed with schizophrenia have external environment, forming functional reorganization (23).
been mixed. Antipsychotics are the frontline treatments for The program had several advantages for the enhancement of
schizophrenia and are effective for psychotic symptoms, but cognitive function, including a simple immersive interactive
their effect on cognitive impairment is neutral (12, 13). In environment, progressive increase in difficulty, motivational
addition, metabolic side effects caused by antipsychotics, competition and physical movements. The hypothesis of this
especially second-generation antipsychotics, may lead to study was that an intensive cognitive training program with an
further deterioration of cognitive impairment (14). Other active virtual reality (VR) serious game can improve cognitive
pharmacological approaches, such as cognitive enhancement function in people diagnosed with schizophrenia. The results are
targeting various neurotransmitter systems, produced small now reported as follows.
effects on global cognition and no significant effects on any
subdomains of cognitive function (15).
On the contrary, fairly intensive cognitive training programs Materials and methods
have had promising findings. Wykes et al. (16) systematically
reviewed 40 studies of cognitive training programs with Study design and participants
2104 participants and found that such programs produced a
small to moderate effect of cognitive improvement in people This was a single-center randomized controlled trial
diagnosed with schizophrenia despite the treatment duration conducted in Chengdu, Sichuan Province, China, from June
and training modality, and these benefits were not compromised 2020 to May 2021. Participants were recruited from inpatients

Frontiers in Psychiatry 02 frontiersin.org

Wang et al. 10.3389/fpsyt.2022.952828

at the mental health center of a tertiary general hospital. psychiatrist. To avoid possible objective bias, the psychiatrist
Clinical nurses referred potential participants to the study in was blinded to the participants’ allocation.
routine medical service. The researchers of this study screened
all referrals for eligibility. Eligible participants were adults
between the ages of 18 and 40, diagnosed with schizophrenia Procedures
by an experienced psychiatrist according to the International
Classification of Disease-10 (ICD-10), without a history of “Fruit Pioneer” was an active VR serious game adapted
head trauma or substance abuse or neurological diseases from popular fruit-cutting games. People diagnosed with
affecting cognitive function, and could understand and speak schizophrenia generally had impaired cognitive function,
Mandarin. This was the first time that many patients had reduced ability to deal with complex situations and reduced
used VR equipment. Therefore, any patient diagnosed with attention. Fruit Pioneer reduced the interference of external
schizophrenia who would like to enroll in the program sound and pictures by using a VR head-mounted display
underwent an experimental session. Exclusion criteria were and headphones. The software was developed using Unity3D
diagnosis of color blindness, feeling negative effects such as (version 2018.3.0f2, Unity Technologies) and ran on a personal
dizziness and fatigue after using VR equipment, failing to computer (HP PC, Intel Core i5-9400F processor, 16 GB DDR4
complete 20 training sessions, participating in other physical 3000 MHz memory, GTX 1660 6GB graphics card, 256 GB
therapy programs to improve cognitive function, or being solid state drive and 1 TB hard disk drive) and the HTC Vive
unable to sign informed consent. (HTC Corporation) VR head-mounted display. The game was
PASS 15.0 software was used to calculate the sample size. played from a first-person perspective, with a swinging panda,
The effect size was set at Cohen’s d = 0.8 based on previous a scoreboard and a circle of fruit-shooting spouts in the users’
studies (16, 24). The two-sided test efficacy was 0.05, and the field of vision (see Figure 1). Headphones of the VR googles
power was 0.80. Thus, the sample size was 50. In the case of a played joyful game sounds that changed with the content and
20%loss to follow-up, 64 participants were recruited according pace of the game. Users held a handle device in each hand,
to the inclusion and exclusion criteria. and the device was instantly connected to the VR googles when
pressed its bottom, which visually changed into two long knives
(see Figure 2). Users were given the task of cutting as many
Randomization and blinding fruits as possible while avoiding iron balls. Fruits may be shot
from any of the spouts. Therefore, users were expected to turn
Sixty-four random numbers were generated by a research around and search for fruits. The fruits were yellow bananas, red
assistant who did not participate in the recruitment and apples, and green watermelons that were common in daily life
intervention of the participants using an online random and varied in color, shape, and size. The smaller the fruit, the
number generator on a website. Each random number more points it would earn after successfully cutting it. Cutting
corresponded to a number from 1 to 64 without repetition, to the iron ball did not penalize points but created turbulence
forming a random number sequence, which was recorded that interfered with the next cut. Each level of the game was
and sealed in opaque envelopes. The even number was set 2 min long. Shooting speed, direction and numbers of fruits can
as the intervention group, and the singular number was be adjusted to the level of difficulty. The further the game went,
set as the control group. Participants were given numbered the more difficult it got. That is, the faster and more scattered the
envelopes in the order in which they were enrolled and
then randomly assigned to either the intervention group or
the control group.
The psychiatric nurse who organized and carried out
participants’ mental rehabilitation activities knew the allocation
of participants. Participants were informed of the activities
they might participate in, but they did not know whether
they were in the intervention group or the control group.
Researchers who collected demographic data and assessed the
outcome measures were blinded to allocation and had no access
to records of participants’ mental rehabilitation activities to
avoid unmasking. Since the VR serious game program was
used as an adjunctive intervention in this study, all participants
still followed the psychiatrist’s advice for medication during
the study. To minimize differences in medication regimens FIGURE 1

while not interfering with participants’ routine treatment, Users’ field of vision from virtual reality (VR) Google.
all participants were selected from patients with the same

Frontiers in Psychiatry 03 frontiersin.org

Wang et al. 10.3389/fpsyt.2022.952828

psychotherapy and group psychiatric rehabilitation. Group

psychiatric rehabilitation activities were organized and guided
by psychiatric nurses in the rehabilitation room, which was
located in a different area from the physical therapy room.
Psychiatric rehabilitation activities were carried out around the
daily life, study, work and social interaction of people diagnosed
with schizophrenia, including psychoeducation about symptom
and medication management, learning or occupational goal
setting and plan making, and social skills training. Such activities
lasted for approximately 45 min, once a day. Participants in
the intervention group could also participate in these activities
if they wanted to.
The arrangement of psychiatric treatment and nursing
care was based on participants’ actual medical needs. During
FIGURE 2
The long knife was controlled by a hand device. hospitalization, each participant was checked for content
and times of participation in psychotherapy and psychiatric
rehabilitation activities according to prescription in the
electronic medical record system to ensure that there was no
difference between the two groups except for the VR serious
game training. All enrolled participants had demographic data
collected by researchers and completed an initial B-CATS
cognitive assessment upon enrollment. Then, B-CATS was
evaluated again before discharge. All researchers received the
same training on study content, methods and assessment tools
prior to the study.

FIGURE 3 Outcomes
The scoreboard displayed the participant’s score and ranking.

A general demographic questionnaire was used to collect

gender, age, education background, and marital status.
fruit appeared, the more likely the iron ball and fruit appeared Primary outcomes were scores of the Brief Cognitive
at the same time. Assessment Tool for Schizophrenia (B-CATS). The B-CATS is
Participants in the intervention group were guided to the a simple instrument to measure approximate cognitive function
physical therapy room for VR serious game training by a that generally takes 12 min to finish. It was constructed by
psychiatric nurse. The psychiatric nurse explained game rules Hurford et al. (25) and contained 4 tests, namely, the Digital
and strategies involved in the Fruit Pioneer and accompanied Symbol Substitution Test (DSST), Trail Making Test part A
participants in case of any adverse event. The game training (TMTA), Trail Making Test part B (TMTB), and Animal Fluency
was one-on-one. To ensure the safety of participants and reduce (AF). In the DSST, participants were presented with a sheet
the sense of insecurity caused by the virtual environment, having 9 symbols paired with digits 1–9 on the top and rows
their activities were confined and protected by a plastic fence of symbols beneath. Participants were asked to pair each symbol
with a diameter of 2 m. Each level of the game lasted 2 min. with its corresponding digit within 120 s. The number of correct
After completing one level, there was a 10-second pause, and pairs was the score. There were 120 symbols on the sheet,
the scoreboard displayed the participant’s score and ranking the first 10 of which were used for examples. Therefore, the
for the level and the highest score of the level created by maximum score for this test was 110. The DSST reflected the
other anonymous participants (see Figure 3). Participants then participant’s work memory. TMTA and TMTB demanded that
chose to repeat the level or start the next level. Each training participants draw a “trail” in numerical order of numbers or
session lasted 20 to 30 min, twice a day. The psychiatric nurse from number to letter (1-A-2-B) without taking the pen off the
recorded the participant’s training sessions. The total number of sheet. Participants were stopped and returned to the last correct
training sessions was at least 20 times for each participant during response when they made a mistake. Time to completion was the
hospitalization. This training program was given to participants score. TMT indicated the participant’s executive function. In the
in addition to standard care. AF part, participants were given 60 s to name as many animals
Participants in the control group received standard as possible. The score was the number of animals named. AF
and routine inpatient psychiatric care, including medication, measures verbal fluency associated with social cognition. The

Frontiers in Psychiatry 04 frontiersin.org

Wang et al. 10.3389/fpsyt.2022.952828

FIGURE 4
Flow diagram of the study.

TABLE 1 Comparison of demographic characteristics between the intervention group and the control group.

Variables (M ± SD)/% t(df)/χ 2 P-value

Intervention group (n = 31) Control group (n = 33)

Gender Male 14 (45.2%) 17 (51.5%) 0.259 0.627

Female 17 (54.8%) 16 (48.5%)
Age (year) 24.61 ± 5.68 26.94 ± 6.27 -1.552 0.126
Length of hospital stay (day) 17.42 ± 4.63 18.03 ± 6.88 -0.414 0.680
Education background Primary school 0 (0%) 2 (6.1%) 3.229 0.760
Junior high school 3 (9.7%) 4 (12.1%)
Senior high school 6 (19.4%) 7 (21.2%)
Junior college 13 (41.9%) 10 (30.3%)
Undergraduate 9 (29.0%) 9 (27.3%)
Graduate 0 (0%) 1 (3.0%)
Marital status Unmarried 21 (67.8%) 19 (57.6%) 0.888 0.626
Married 9 (29.0%) 12 (36.4%)
Divorced 1 (3.2%) 2 (6.0%)

Frontiers in Psychiatry 05 frontiersin.org

Wang et al. 10.3389/fpsyt.2022.952828

B-CATS presented good divergent validity, test-rest reliability P < 0.05 indicates that the difference is statistically significant.
and internal consistency (25). In addition, it can be easily Count data were described by frequency and composition ratio
administered by medical staff with proper training, suitable for and compared by the Fisher’s exact test. Measurement data
use in this study. with a normal distribution were described by the mean plus
or minus the standard deviation, and measurement data with
a non-normal distribution were described by the median and
Ethical consideration first quartile and third quartile. The Shapiro–Wilk test was
used for normality testing. An independent t test was used to
This study was ethically approved by the Biomedical compare the data with a normal distribution. If the data did
Ethics Committee of West China Hospital, Sichuan University not obey a normal distribution, the Mann–Whitney U test was
(reference: 2019-468). All methods were carried out in used for comparison. To ensure the robustness of the findings,
accordance with relevant guidelines and regulations.(e.g., independent t test was used for sensitivity analysis after log-
Helsinki declaration). The procedures and content of the study transformation of skewed outcomes. Analyzes were done by
were explained to all participants. Participants were informed complete case analysis.
that they could withdraw from the study at any time, and
it would not interfere with their medical services. Written
informed consent was obtained before any interventions. This
trial is registered with the Chinese Clinical Trial Registry, Results
number ChiCTR1900028041.
Comparison of demographic
characteristics
Data analysis
In this study, 64 participants were finally included and
EpiData3.0 software was used to input and manage randomly assigned to the intervention group (n = 31) and the
demographic data and neurocognitive function assessment data. control group (n = 33) (see Figure 4). No participants withdrew
SPSS 21.0 statistical analysis software was used for data analysis. midway or failed to complete 20 sessions of training. The

TABLE 2 Comparison of baseline cognitive function between the intervention group and the control group.

Variables (M ± SD)/[M(Q1,Q3)] t/Z P-value

Intervention group (n = 31) Control group (n = 33)

DSSTa 52.97 ± 14.84 43.30 ± 14.28 2.656 0.880

TMTAb 41.00 (30.00, 51.00) 45.00 (31.00, 62.50) −0.820 0.412
TMTBb 92.00 (63.00, 118.00) 92.00 (76.00, 180.50) −1.673 0.094
AFb 19.00 (18.00, 21.00) 18.00 (14.00, 22.50) −0.936 0.349

(M ± SD), (mean ± standard deviation); [M(Q1-Q3)], [median(first quartile, third quartile)]; DSST, digital symbol substitution test; TMTA, trail making test part A; TMTB, trail making
test part B; AF, animal fluency.
a Means that the difference was assessed by independent t test.
b Means that the difference was assessed by Mann–Whitney U test.

TABLE 3 Comparison of cognitive function between the intervention group and the control group after intervention.

Variables (M ± SD)/[M(Q1,Q3)] t/Z P-value Effect size (Cohen’s d)

Intervention group (n = 31) Control group (n = 33)

DSSTa 59.19 ± 16.78 45.64 ± 14.51 3.463 0.001 0.87

TMTAb 31.00 (28.00, 50.00) 41.00 (32.50, 59.00) −2.272 0.023 0.59
TMTBb 68.00 (46.00, 103.00) 90.00 (70.00, 144.50) −2.365 0.018 0.62
AFb 21.00 (17.00, 25.00) 18.00 (15.00, 23.00) −1.394 0.163 0.35

(M ± SD), (mean ± standard deviation); [M(Q1-Q3)], [median(first quartile, third quartile)]; DSST, digital symbol substitution test; TMTA, trail making test part A; TMTB, trail making
test part B; AF, animal fluency.
a Means that the difference was assessed by independent t test.
b Means that the difference was assessed by Mann–Whitney U test.

Frontiers in Psychiatry 06 frontiersin.org

Wang et al. 10.3389/fpsyt.2022.952828

average VR serious game training sessions in the intervention indicating that the two groups were comparable. At the same
group were 25.84 (standard deviation = 4.03). The demographic time, there were no significant differences in baseline B-CATS
data of the participants in the two groups were compared. results, suggesting that the two groups had the same degree
There was no significant difference in sex, age, length of of cognitive impairment prior to intervention. The results of
hospital stay, education background or marital status between this study showed that the intensive VR serious game training
the intervention group and the control group, as shown in program significantly improved participant’s working memory
Table 1. and executive function, but had little effect on social cognition.
People with schizophrenia have impaired working memory,
which means that their ability to temporarily store and process
Baseline cognitive function information is reduced (26). In this study, the DSST scores of
people diagnosed with schizophrenia in the intervention group
Before comparing the baseline cognitive function of the were significantly higher than those in the control group after
intervention group and the control group, the Shapiro–Wilk test intervention, indicating that intensive active VR serious game
was performed on B-CATS scores. The results showed that only training improved working memory in the intervention group.
the DSST scores obeyed a normal distribution (p = 0.836), while This was consistent with a previous study showing that serious
the TMTA (p < 0.001), TMTB (p < 0.001), and AF (p = 0.013) game training enhanced visuospatial working memory (27).
scores did not. Therefore, an independent t test was used to There are two strategies commonly used in the DSST. One way
compare the DSST, and the Mann–Whitney U test was used to is to look for the digit corresponding to each symbol in the
compare the TMTA, TMTB, and AF between the two groups. example during the whole test process. The other is to memorize
There were no significant differences between the two groups symbols and their corresponding digits first and then fill in the
in the baseline scores of the DSST, TMTA, TMTB, and AF. The corresponding digits of symbols in the blank space. Usually,
results are shown in Table 2. the latter strategy accomplishes more. This VR serious game
used the latter strategy as the training paradigm. Before the
game, participants were informed of scores of different fruits
Comparison of cognitive function after (symbols), with an emphasis on the goal of the game, namely,
intervention to get as many points as possible in a limited time. At the end of
each game, participants could compare their scores with scores
The results of the Shapiro–Wilk test showed that the DSST and rankings on the scoreboard created by other players. The
scores obeyed a normal distribution (p = 0.110), while the TMTA smaller the difference, the more correct the participant’s strategy
(p = 0.001), TMTB (p < 0.001), and AF (p < 0.001) scores did was. To obtain more scores, participants needed to quickly
not. Thus, an independent t test was used to compare the DSST, respond to the fruits with high scores and constantly optimize
and the Mann–Whitney U test was used to compare the TMTA, the strategy during the training sessions to achieve the training
TMTB, and AF between the two groups. The DSST scores of and improvement of working memory.
participants in the intervention group were significantly higher After intervention, the test time of TMTA and TMTB in
than those in the control group. Participants in the intervention the intervention group was significantly shorter than that in the
group completed TMTA and TMTB significantly faster than control group. TMT reflects executive function by evaluating
those in the control group. There was no significant difference visual search, cognitive flexibility and psychomotor speed (28).
in AF scores between the two groups. Details of scores were The results of this study indicated that VR serious game training
shown in Table 3. Distribution of outcomes after intervention improved the executive function of the intervention group,
were shown in Figure 5 and changes of B-CATS scores from which was consistent with previous studies. Rozental-Iluz et al.
baseline were shown in Figure 6. (29) found that interactive video game training increased motor
Scores of TMTA, TMTB, and AF were log-transformed and speed and cognitive flexibility in individuals with chronic
compared with independent t test to ensure the robustness of the stroke. Shimizu et al. (30) demonstrated that interactive sports
findings. Results were the same that was, the scores of TMTA serious game training was correlated with increased executive
and TMTB in the intervention group were significantly lower function performance in people diagnosed with schizophrenia.
than those of the control group, and there was no significant People diagnosed with schizophrenia showed executive function
difference in the AF scores between the two groups. Results were deficits manifested as difficulty in making and implementing
shown in Table 4. plans, solving problems, and completing target tasks (31). The
cutting of fruits in this study required participants to conduct
a visual search of the target fruit and then perform the cutting
Discussion by quickly identifying and integrating different properties of
the target. In addition, constant attempts to avoid iron balls
There was no significant difference in the demographic trained inhibition. The potential underlying rationale is that
data between the intervention group and the control group, repeated VR target cutting stimulates the central nervous

Frontiers in Psychiatry 07 frontiersin.org

Wang et al. 10.3389/fpsyt.2022.952828

FIGURE 5
Scores on the four Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) tests after intervention.

FIGURE 6
Scores on the four Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) tests. (A) DSST, (B) TMTA, (C) TMTB, (D) AF.

Frontiers in Psychiatry 08 frontiersin.org

Wang et al. 10.3389/fpsyt.2022.952828

TABLE 4 Sensitivity analysis using independent t test for log-transformed skewed outcomes.

Variables (M ± SD) t P-value Effect size (Cohen’s d)

Intervention group (n = 31) Control group (n = 33)

TMTA 3.52 ± 0.40 3.76 ± 0.39 −2.522 0.014 0.61

TMTB 4.28 ± 0.57 4.61 ± 0.55 −2.351 0.022 0.59
AF 3.02 ± 0.35 2.90 ± 0.28 1.613 0.112 0.38

(M ± SD), (mean ± standard deviation); DSST, digital symbol substitution test; TMTA, trail making test part A; TMTB, trail making test part B; AF, animal fluency.

system to generate new synaptic connections or repair existing standard psychiatric care can significantly improve working
connections, thus improving the executive function of patients, memory and executive function in people diagnosed with
according to the theory of neuroplasticity. schizophrenia. However, global cognition enhancement
There was no significant difference in AF scores between the requires more comprehensive serious game training strategies.
intervention group and the control group. AF measures verbal
fluency, which is closely related to social function (32). Grimes
et al. (33) found that verbal fluency was stable across multiple
Relevance for clinical practice
stages of schizophrenia even with antipsychotic medications and
suggested that it could be a neurocognitive endophenotype for
Intensive active virtual reality serious games with attention,
schizophrenia, partly self-explaining its stability. Even physical
memory and reaction speed as the main training targets
exercise, which was strongly advised for cognitive improvement,
can significantly improve neurocognition, including working
had only a marginally significant effect on verbal fluency
memory and executive function. However, such a training
(34). In contrast, psychosocial interventions, which encouraged
strategy had limited influence on social cognition. These
participants to socialize with others, improved verbal fluency
two aspects of cognitive function require different training
(35, 36). This probably explained the ineffectiveness of the active
strategies. Therefore, when mental health professionals try to
VR serious game training in this study. Unlike psychosocial
design a program to improve the global cognitive function
interventions, this training program barely involved any
of people diagnosed with schizophrenia, they need to identify
language training of participants. It was suggested that cognitive
the cognitive domains to be enhanced and then develop
training needed to be targeted, and each subdomain required
corresponding serious game training strategies.
different training strategies.
This trial has some limitations. First, participants and
researchers responsible for the interventions were not blinded.
There was a perceptible difference in the activities between the Data availability statement
intervention group and the control group. Although we set
the activities in different rooms to reduce the direct impact, The raw data supporting the conclusions of this article will
it was possible that the participants were subjectively affected. be made available by the authors, without undue reservation.
We blinded the researchers who evaluated the outcomes to
decrease subjective bias. Second, the active feature of the
VR serious game training (such as standing and turning Ethics statement
around during the training) could contribute to the positive
outcome of this study. However, indicators reflecting physical The studies involving human participants were
exercise were not monitored in this trial, so further studies reviewed and approved by Medical Ethics Committee
are needed. Third, the sample size of this study was calculated of West China Hospital, Sichuan University. The
and adequate for a randomized controlled trial, but the overall patients/participants provided their written informed consent
representation of cognitive function in people diagnosed with to participate in this study.
schizophrenia was limited.

Author contributions
Conclusion
XW, XM, and JY contributed to the conception and
The results of this study showed that providing intensive design of the study. XW and XK organized and implemented
active virtual reality serious game training in addition to the intervention. XW performed the statistical analysis and

Frontiers in Psychiatry 09 frontiersin.org

Wang et al. 10.3389/fpsyt.2022.952828

wrote the first draft of the manuscript. XK, XM, and JY Conflict of interest
wrote sections of the manuscript. All authors contributed to
manuscript revision, read, and approved the submitted version. The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Funding
The reviewer CG and handling editor declared their
This research is funded by the Department of Science shared affiliation.
and Technology of Sichuan Province, China (Grant Number:
2018SZ0198).
Publisher’s note
Acknowledgments All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
All rights of the Fruit Pioneer are with the authors of this organizations, or those of the publisher, the editors and the
study. The authors would like to thank Professor Wei Deng for reviewers. Any product that may be evaluated in this article, or
helping to develop the virtual reality serious game software and claim that may be made by its manufacturer, is not guaranteed
insightful discussions on the mechanism of this program. or endorsed by the publisher.

References
1. World Health Organization. Schizophrenia. Geneva: World Health a network meta-analysis. Eur J Clin Pharmacol. (2013) 70:127–34. doi: 10.1007/
Organization (2019). s00228-013-1600-y
2. Carrà G, Crocamo C, Angermeyer M, Brugha T, Toumi M, Bebbington P. 14. MacKenzie NE, Kowalchuk C, Agarwal SM, Costa-Dookhan KA, Caravaggio
Positive and negative symptoms in schizophrenia: a longitudinal analysis using F, Gerretsen P, et al. Antipsychotics, metabolic adverse effects, and cognitive
latent variable structural equation modeling. Schizophr Res. (2019) 204:58–64. doi: function in schizophrenia. Front Psychiatry. (2018) 9:622. doi: 10.3389/fpsyt.2018.
10.1016/j.schres.2018.08.018 00622
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental 15. Sinkeviciute I, Begemann M, Prikken M, Oranje B, Johnsen E, Lei WU, et al.
Disorders. 5th ed. Washington, DC: American Psychiatric Association (2013). doi: Efficacy of different types of cognitive enhancers for patients with schizophrenia: a
10.1176/appi.books.9780890425596 meta-analysis. NPJ Schizophr. (2018) 4:22. doi: 10.1038/s41537-018-0064-6
4. Kahn RS, Keefe RS. Schizophrenia is a cognitive illness. JAMA Psychiatry. 16. Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P. A meta-analysis
(2013) 70:1107–12. doi: 10.1001/jamapsychiatry.2013.155 of cognitive remediation for schizophrenia: methodology and effect sizes. Am J
Psychiatry. (2011) 168:472–85. doi: 10.1176/appi.ajp.2010.10060855
5. Seidman LJ, Mirsky AF. Evolving notions of schizophrenia as a developmental
neurocognitive disorder. J Int Neuropsychol Soc. (2017) 23:881–92. doi: 10.1017/ 17. Firth J, Stubbs B, Rosenbaum S, Vancampfort D, Malchow B, Schuch F, et al.
s1355617717001114 Aerobic exercise improves cognitive functioning in people with schizophrenia: a
systematic review and meta-analysis. Schizophr Bull. (2016) 43:546–56. doi: 10.
6. Schaefer J, Giangrande E, Weinberger DR, Dickinson D. The global cognitive
1093/schbul/sbw115
impairment in schizophrenia: consistent over decades and around the world.
Schizophr Res. (2013) 150:42–50. doi: 10.1016/j.schres.2013.07.009 18. Zayeni D, Raynaud J, Revet A. Therapeutic and preventive use of video games
in child and adolescent psychiatry: a systematic review. Front Psychiatry. (2020)
7. Vaskinn A, Andersson S, Østefjells T, Andreassen OA, Sundet K. Emotion
11:36. doi: 10.3389/fpsyt.2020.00036
perception, nonsocial cognition and symptoms as predictors of theory of mind in
schizophrenia. Compr Psychiatry. (2018) 85:1–7. doi: 10.1016/j.comppsych.2018.05. 19. Naismith LM, Cavalcanti RB. Validity of cognitive load measures in
002 simulation-based training. Acad Med. (2015) 90:S24–35. doi: 10.1097/acm.
0000000000000893
8. Green MF. Impact of cognitive and social cognitive impairment on functional
outcomes in patients with schizophrenia. J Clin Psychiatry. (2016) 77(Suppl. 2):8– 20. Van Dis EA, Van Veen SC, Hagenaars MA, Batelaan NM, Bockting CL,
11. doi: 10.4088/jcp.14074su1c.02 Van den Heuvel RM, et al. Long-term outcomes of cognitive behavioral therapy
for anxiety-related disorders. JAMA Psychiatry. (2020) 77:265–73. doi: 10.1001/
9. Tominaga T, Tomotake M, Takeda T, Ueoka Y, Tanaka T, Watanabe jamapsychiatry.2019.3986
S, et al. Relationship between social and cognitive functions in people with
schizophrenia. Neuropsychiatr Dis Treat. (2018) 14:2215–24. doi: 10.2147/ndt.s17 21. Holtz BE, Murray K, Park T. Serious games for children with chronic diseases:
1207 a systematic review. Games Health J. (2018) 7:291–301. doi: 10.1089/g4h.2018.0024

10. Helldin L, Mohn C, Olsson A, Hjärthag F. Neurocognitive variability 22. Nascimento KG, Ferreira MB, Felix MM, Nascimento JD, Chavaglia SR,
in schizophrenia spectrum disorders: relationship to real-world functioning. Barbosa MH. Effectiveness of the serious game for learning in nursing: systematic
Schizophr Res. (2020) 20:100172. doi: 10.1016/j.scog.2020.100172 review. Rev Gaúcha Enferm. (2021) 42:e20200274. doi: 10.1590/1983-1447.2021.
20200274
11. Cook EA, Liu NH, Tarasenko M, Davidson CA, Spaulding WD. Longitudinal
relationships between neurocognition, theory of mind, and community functioning 23. Konorski J. Conditioned Reflexes and Neuron Organization. Cambridge:
in outpatients with serious mental illness. J Nerv Ment Dis. (2013) 201:786–94. Cambridge University Press (1948).
doi: 10.1097/nmd.0b013e3182a2140b 24. Freeman D, Haselton P, Freeman J, Spanlang B, Kishore S, Albery E, et al.
12. Nielsen RE, Levander S, Kjaersdam Telléus G, Jensen SO, Østergaard Automated psychological therapy using immersive virtual reality for treatment of
Christensen T, Leucht S. Second-generation antipsychotic effect on fear of heights: a single-blind, parallel-group, randomised controlled trial. Lancet
cognition in patients with schizophrenia-a meta-analysis of randomized Psychiatry. (2018) 5:625–32. doi: 10.1016/S2215-036630226-8
clinical trials. Acta Psychiatr Scand. (2015) 131:185–96. doi: 10.1111/acps.1
25. Hurford IM, Ventura J, Marder SR, Reise SP, Bilder RM. A 10-minute
2374
measure of global cognition: validation of the brief cognitive assessment tool for
13. Désaméricq G, Schurhoff F, Meary A, Szöke A, Macquin-Mavier I, Bachoud- schizophrenia (B-CATS). Schizophr Res. (2018) 195:327–33. doi: 10.1016/j.schres.
Lévi AC, et al. Long-term neurocognitive effects of antipsychotics in schizophrenia: 2017.08.033

Frontiers in Psychiatry 10 frontiersin.org

Wang et al. 10.3389/fpsyt.2022.952828

26. Wu D, Jiang T. Schizophrenia-related abnormalities in the triple network: a their unaffected first-degree relatives, and healthy participants. Int J
meta-analysis of working memory studies. Brain Imaging Behav. (2019) 14:971–80. Neuropsychopharmacol. (2020) 23:731–7. doi: 10.1093/ijnp/pyaa052
doi: 10.1007/s11682-019-00071-1
32. Ardila A. A cross-linguistic comparison of category verbal fluency test
27. Toril P, Reales JM, Mayas J, Ballesteros S. Video game training enhances (Animals): a systematic review. Arch Clin Neuropsychol. (2019) 35:213–25. doi:
visuospatial working memory and episodic memory in older adults. Front Hum 10.1093/arclin/acz060
Neurosci. (2016) 10:206. doi: 10.3389/fnhum.2016.00206
33. Grimes KM, Foussias G, Remington G, Kalahani-Bargis K, Zakzanis KK.
28. Bowie CR, Harvey PD. Administration and interpretation of the Stability of verbal fluency in outpatients with schizophrenia. Psychiatry Res. (2021)
trail making test. Nat Protoc. (2006) 1:2277–81. doi: 10.1038/nprot.20 295:113528. doi: 10.1016/j.psychres.2020.113528
06.390
34. Huang Y, Hung C, Hsu S, Lin P, Lee Y, Chong M, et al. Effects of aerobic
29. Rozental-Iluz C, Zeilig G, Weingarden H, Rand D. Improving executive walking on cognitive function in patients with schizophrenia: a randomized
function deficits by playing interactive video-games: secondary analysis of a controlled trial. J Psychiatr Res. (2021) 134:173–80. doi: 10.1016/j.jpsychires.2020.
randomized controlled trial for individuals with chronic stroke. Eur J Phys Rehabil 12.062
Med. (2016) 52:508–15.
35. Shimada T, Nishi A, Yoshida T, Tanaka S, Kobayashi M. Development
30. Shimizu N, Umemura T, Matsunaga M, Hirai T. An interactive of an individualized occupational therapy programme and its effects on the
sports video game as an intervention for rehabilitation of community- neurocognition, symptoms and social functioning of patients with schizophrenia.
living patients with schizophrenia: a controlled, single-blind, crossover Occup Ther Int. (2016) 23:425–35. doi: 10.1002/oti.1445
study. PLoS One. (2017) 12:e0187480. doi: 10.1371/journal.pone.018
36. Shimada T, Ohori M, Inagaki Y, Shimooka Y, Sugimura N, Ishihara I, et al. A
7480
multicenter, randomized controlled trial of individualized occupational therapy for
31. Kataoka Y, Shimada T, Koide Y, Okubo H, Uehara T, Shioiri T, et al. patients with schizophrenia in Japan. PLoS One. (2018) 13:e0193869. doi: 10.1371/
Differences in executive function among patients with schizophrenia, journal.pone.0193869

Frontiers in Psychiatry 11 frontiersin.org