Physiology-based Virtual Reality Training for Social Skills in Schizophrenia
Phase: NA
Conditions: Schizophrenia, Schizo Affective Disorder, Social Skills
Sponsor: Vanderbilt University

09/19/2024  
 
R33 MH106748 Physiology-based virtual reality training for social skills in 
schizophrenia  
 
NCT04005794 
 
(Virtual Reality Training for Social Skills in Schizophrenia - Comparison With 
Cognitive Training) 
 
Date: 09/19/2024 
    
  
 
 

09/19/2024  
Study Protocol 
 
We were able to show the target engagement in the R21 phase of this study. The major goal of 
the R33 phase is to prepare for a future randomized controlled clinical trial (RCT) by piloting a 
feasibility study that includes an active control arm and multimodal pre- and post-treatment 
measures. We aimed to achieve the following: (1) test the feasibility of recruiting, randomizing 
and retaining patients for VR social skills training; 2) compare the social skills training VR 
compared an active control VR game by measuring behavioral and neural changes after VR 
intervention.  
 
R33 PROJECT DESIGN  
This is a small pilot study to compare the outcome measures after the VR social skills training 
compared with an active control video game. Participants with schizophrenia (SZ) undergo 
training. Participants with schizophrenia are randomly assigned to the social skills VR condition 
or the active control condition at baseline.  After completing all the baseline assessments 
including clinical symptoms ratings, social cognitive assessments, and resting state fMRI scan, 
participants are asked to visit the lab for 8 sessions (twice a week) to complete the VR training 
or the active control condition. After 8 sessions, there is a post-training assessment that 
includes symptoms ratings, social cognitive assessments and resting state fMRI scan. Then 
participants cross over to the other condition for 8 sessions, after which there is a final post-
training assessment.  Demographically matched control participants are recruited to obtain 
comparison data but they do not undergo any training. Research staff conducting clinical 
symptoms and social functions assessments are blind to the VR training or control condition 
assignment.  
 
VR Condition: The same procedure as outlined in R21 phase with the determined optimal dose 
of 8 sessions administered over 4-5 weeks. 
 
Active Control Condition: We control for the number of lab visits, duration of game playing 
and computer use in the active control group by administering a commercially available video 
games which do not require any simulated social interactions but instead, support cognition.  
 
Participants: 
 
 
This proposal involves testing individuals with schizophrenia (SZ), and healthy control 
subjects (CO). All subjects are recruited from Nashville area. The following general 
inclusion/exclusion criteria apply to all subjects: (1) no diagnosed organic brain disease, brain 
lesions, history of head traumas, hormonal disorders, neurological disorders or other conditions 
that involve the degeneration of the central nervous system (e.g. multiple sclerosis), (2) no 
substance/alcohol abuse/dependence during the past 1 year, (3) no tardive dyskinesia, (4) 
WASI IQ> 85. Low IQ makes it less likely that the participants understand the instructions and 
comply and thus, might introduce confounding factors. Since we need to establish the initial 
feasibility and acceptability, it is essential that they understand the training instructions. 
Therefore, we only included those participants with IQ > 85 and those who are able to travel to 

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the lab independently. Any co-existing medical conditions (e.g., diabetes), smoking habits, and 
medications were noted. Diagnostic interviews (SCID) were conducted for Axis I for all subjects. 
 
 
Inclusion/exclusion criteria for schizophrenia group: Participants were recruited 
from outpatient day facilities in Nashville. DSM-5 criteria were used to diagnose SZ. Those with 
a history of head injury, substance abuse, neurological diseases (e.g., stroke, tumors), 
hormonal disorders (e.g. Cushing’s disease) or IQ<85 will be excluded. All patients were taking 
antipsychotic medications. When someone is very psychotic, any social remediation training is 
not going to be effective. Recruiting outpatients who are stabilized on medication, allowed us to 
work with the population whose psychotic symptoms are partially in remission but are still 
experiencing significant social cognitive impairments. The range of symptoms scores of our 
outpatient sample in the past 14 years in Nashville is very comparable to the scores reported by 
other groups. The mean SAPS score of our SZ outpatients from the past 14 years was 15.34 
(S.D.= 8.36) and the mean SANS was 23.71 (S.D.=14.73). These scores are almost identical to 
the published mean SAPS (16.8, s.d.=14.2) and SANS (23.0, s.d.=14.6) scores from the FBIRN 
consortium143. For this R33 study, if the SAPS or SANS score is 1 s.d. above the mean of our 
typical outpatient sample (i.e. SAPS > 23; SANS > 38), we planned to place that patient on a 
wait list until his/her symptom scores fall within 1 s.d. of the mean. This additional precaution 
should be able to address potential concerns that psychotic individuals may be adversely 
affected by virtual reality video games. (See below). One note of concern is the potential 
adverse effects of the COVID pandemic. This study was on hold for 2 years during the 
pandemic because we were unable to open the lab to test and train participants due to the 
concerns of infection. After the study was able to start in 2021, we noted worsening of physical 
health of the SZ individuals who had consented to participate prior to the pandemic. 
Inclusion/exclusion criteria for the healthy control group: Healthy participants were 
recruited from the Vanderbilt University web-based recruitment panel and from Nashville Metro 
area via signs placed in public buildings (e.g. supermarkets, Laundromats, gyms, cafes). 
Exclusion criteria were: Axis I psychotic disorders in themselves or their families (e.g. 
schizophrenia, bipolar disorder), history of head injury, substance abuse, neurological diseases 
(e.g., stroke, tumors), hormonal disorders (e.g. Cushing’s disease) and IQ<85.  
Additional screening for neuroimaging in R33: There are further exclusion criteria for 
fMRI in the R33 phase because those at primary risk from exposure to high-intensity magnetic 
fields must be excluded. Exclusion criteria are implanted medical devices (e.g. pacemakers, 
cochlear implants, IUDs), implanted paramagnetic prostheses, and augmentations (e.g. steel 
pin). People at secondary risk are also excluded (e.g. asthma, heart disease, diabetes etc). 
Potential participants must fill out the standard questionnaire used with all patients undergoing 
MRI at the Vanderbilt University Medical Center. If a potential participant meets the criteria for 
inclusion in the fMRI component, he/she will go through the informed consent procedure for 
neuroimaging. If a participant does not meet the inclusion criteria for fMRI part, he/she will not 
participate in the neuroimaging but will participate in all other parts provided that he/she meets 
the inclusion/exclusion criteria described above. 
Age range: Included age range was 18 and 65. In our actual recruited sample the 
youngest participant was 20. Aging increases the likelihood of introducing confounding factors 
such as cognitive decline, dementia, hormonal changes and others. This age group will be 

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familiar with video games and computers. This is important because the VR training and active 
control training are similar to video games. 
Ethnic composition and diversity: Nashville metropolitan area is increasingly 
ethnically diverse. We tried to recruit ethnically representative samples of SZ and CO. In our 
past studies in Nashville, about 20% of our participants were African-Americans.  
Gender: We aimed to recruit 50% women.  
 
Procedure: All participants undergo baseline assessments at T1, including fMRI. The research 
staff conducting assessments are blind to the treatment groups and those who supervise the 
training session do not do assessments. SZ play the VR game or active control game in the lab. 
The VR dosing was determined in the R21 phase (8 sessions). After the completion of the 
training, they are given the post-training assessments and then switch over to the other 
condition for 8 sessions. We use the same dose for the active control condition. The VR and 
control game performance scores are saved at each session. To boost adherence, we text 1 
day before and 2 hours before the visit. Subjects are paid per session and receive a small 
bonus at the end of the training. An exit interview is conducted to find out about acceptability 
and engagement. 
 
Measures: At baseline (T1), we assess social cognitive functions, symptoms and conduct a 
resting state fMRI scan. To elucidate the mechanism of change, we focus on the social attention 
and the integrity of the social brain network that supports social cognition. Training begins within 
a week of completing the assessments. Within a week of the completion of the training, we 
conduct post-treatment assessments. Next, SZ participants cross over to the other condition 
and complete 8 sessions, after which they undergo another post-training assessments.  Control 
participants complete only the baseline assessments.  
 
Data Analysis Behavioral Measures: The same general framework as those described for the 
R21 phase were used. We use univariate and multivariate mixed effects models (LMMs) to 
assess the effects of the VR intervention relative to the control game condition on the social 
assessment and symptom measures and other measures noted above (see below for fMRI). 
We assess effects both at post-Intervention for the VR condition and compare them with the 
post-intervention after the active control condition. As described in the R21 phase, we will also 
conduct intensive analyses within the VR condition of the trajectory of performance across 8 
sessions of the social skills training. Using structural equation modelling approaches that are 
appropriate for the moderate sample size, we will further conduct mediational analyses 
assessing the important question of whether changes in social attention and in the trajectory of 
performance during training mediate the effects of treatment on social functioning and 
symptoms. As in the R21 phase, we will also compare post-treatment SZ to normative 
distributions, and model drop-out and attrition.  
 
Neuroimaging data: VR task provides extensive opportunities to exercise social attention and 
simulation. We will examine the activity of the pSTS, IPL, and IFG in relation to social attention 
and social functioning. Our past work indicates that action imitation and simulation deficits in 
SZ38,39,117 but repeated practice improve performance39. Furthermore, a recent study showed 

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that simulation work exercises in VR significantly improved work function in real life. We will 
examine resting state functional connectivity data in relation to the primary outcome measures. 
Data Acquisition: A Philips Intera Achieva 3T scanner is used to collect high-resolution T1 
anatomical images (170 slices; 1x1x1 mm), and T2*-weighted functional images parallel to the 
AC-PC line (gradient-echo T2*-weighted EPI; 25 slices; TR=2000ms;TE=35ms,flip angle=79˚; 
FOV=240x240mm2; voxel size =1.875x1.875x5mm3). FMRI data analysis: BrainVoyager 
QX1.1 is used. Anatomical volumes are transformed into a common stereotactic space91, and 
functional volumes for each subject are aligned to the transformed anatomical volumes. 
Standard pre-processing is performed: temporal high-pass temporal frequency filtering, linear 
de-trending, 3D motion correction, slice scan time correction, and spatial smoothing with a 6mm 
Gaussian kernel (full width half-maximum). Individual subject analyses are performed using a 
GLM with the 6 experimental conditions entered as regressors, and data are collapsed across 
runs. First, we compare SZ vs. CO at baseline to determine the integrity of the social brain 
network (group-by-instruction-by-stimulus type mixed-effects analysis) at resting state. 
Statistical maps are created for each group separately and for the group comparison. Multiple 
comparisons are corrected at p=.05 by Monte Carlo simulations to arrive at a cluster threshold. 
We will compare the pre- and post-treatment cortical activity patterns for each treatment 
regimen. We will also assess the relation between changes in activation of the social brain 
network and in social attention on the behavioral task and whether such changes predict 
changes on social outcome measures.