Can immersive virtual reality magnify treatment outcomes of computerized script training on Cantonese speakers with chronic aphasia? Protocol of a randomized controlled trial.

Can immersive virtual reality magnify treatment outcomes of computerized script training on Cantonese speakers with chronic aphasia? Protocol of a randomized controlled trial - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice PLoS One . 2026 Jun 2;21(6):e0350390. doi: 10.1371/journal.pone.0350390 Can immersive virtual reality magnify treatment outcomes of computerized script training on Cantonese speakers with chronic aphasia? Protocol of a randomized controlled trial Winsy Wing Sze Wong 1, * , Donald Shi Pui Li 2 , Kenneth Ngai Kuen Fong 3 , Peter Hiu Fung Ng 4 , Hoi Tsz Karen Kwok 1 Editor: Jan Christopher Cwik 5 Author information Article notes Copyright and License information 1 Department of Language Science and Technology, Faculty of Humanities, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China 2 Department of Cognitive Science, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, Maryland, United States of America 3 Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China 4 Department of Computing, Faculty of Engineering, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, China 5 Hochschule Niederrhein - Campus Mönchengladbach: Hochschule Niederrhein - Campus Monchengladbach, GERMANY ✉ * E-mail: winsyws.wong@polyu.edu.hk Competing Interests: NO authors have competing interests. Roles Winsy Wing Sze Wong : Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing Donald Shi Pui Li : Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing Kenneth Ngai Kuen Fong : Data curation, Formal analysis, Funding acquisition, Methodology, Writing – review & editing Peter Hiu Fung Ng : Data curation, Formal analysis, Funding acquisition, Methodology, Writing – review & editing Hoi Tsz Karen Kwok : Data curation, Formal analysis, Project administration, Resources, Writing – original draft, Writing – review & editing Jan Christopher Cwik : Editor Received 2025 Oct 21; Accepted 2026 May 11; Collection date 2026. © 2026 Wong et al This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMC Copyright notice PMCID: PMC13229358  PMID: 42228712 This article has been corrected. See PLoS One. 2026 Aug 26;21(8):e0357039 . Abstract Background Aphasia persists in 20% of the stroke population. Speech therapy has been suggested to benefit the functional communication of people with aphasia (PWA). Virtual reality (VR) has been widely applied in motor/cognitive rehabilitation of stroke patients. The current proposal investigates the efficacy of VR-based computerized script training on the functional communication of PWA. Methods A three-armed assessor-blinded randomized controlled trial (RCT) will recruit 120 PWA. They will be randomly assigned to 1) VR-based computerized script training, 2) computerized script training without VR, or 3) no treatment control. In the VR condition, PWA will practice in VR depicting everyday contexts, while in the non-VR group, PWA will practice with static photos. PWA in the control group will be assessed without training. Outcomes on functional communication, aphasia severity, and quality of life will be compared before/after treatment. The findings will provide empirical evidence to inform the development of effective and ecologically valid interventions for PWA. Trial registration ClinicalTrials.gov NCT06722092 Introduction Aphasia, a deficit in language comprehension and production predominantly caused by a stroke, affects about 20% of post-stroke populations in the chronic stage [ 1 ]. It imposes a significant impact on the communication of people with aphasia (PWA) in different social/vocational contexts, affecting their well-being [ 2 ]. A Cochrane review [ 3 ] concluded that speech-language therapy (SLT), in contrast with social support or communication stimulation that does not target specific therapeutic goals, is effective in reducing aphasia severity and improving functional communication (i.e., language use in interactive, multimodal, and situated contexts [ 4 ]). Different interventions, with targets at varying levels of linguistic complexity, delivered on a group/individual basis, conducted by real-person clinicians/computers, have been developed and shown to be beneficial for the communication and language processing of PWA. However, treatment methods vary in effect size, and there is limited understanding of the ‘active ingredients’ within these protocols that play critical roles in enhancing treatment outcomes. Factors, including dose (see a review by Harvey et al. [ 5 ]), treatment intensity [ 6 ], and cueing conditions [ 7 ], that affect treatment effectiveness/efficiency have been investigated. Alternatively, another research direction concerns the application of cutting-edge technologies in treatment delivery, e.g., mobile apps and virtual reality (VR), and their potential to further enhance treatment outcomes compared with conventional SLT. VR, defined as the use of computer technology to create a realistic environment, enables users to immerse themselves, interact, and experience a sense of presence in the simulated environment [ 8 ]. The application of VR in rehabilitation is more than a novel and enjoyable experience; its features and the underlying reasons for promoting learning/treatment outcomes are supported by neurolinguistic theories. It is argued that the immersive experience and multi-sensory feedback provided by VR allow users to perform motor training and observe the actions displayed by avatars, which would subsequently activate the mirror neuron system [ 9 ] and promote recovery [ 10 ]. Another neurolinguistic account, known as the theory of embodied cognition, explains that the multimodal interactions between the user and the virtual environment provided by VR in a social context may facilitate conceptual processing and its representation (see Mahon & Caramazza [ 11 ] for a discussion). In addition, there is both neural and behavioral evidence that the sensory experience in VR can change neural representations and behavioral decisions outside VR when neurologically healthy participants encounter similar situations in the future [ 12 ]. Although the theoretical account of VR in language rehabilitation for post-stroke aphasia remains inconclusive, how VR benefits second-language learning from an embodied and social cognition perspective has been discussed based on behavioral and neuroimaging findings [ 13 ]. Given that the sense of embodiment and presence in VR is also readily experienced by people suffering from stroke [ 14 ], it is, therefore, reasonable to postulate that stroke patients may likewise benefit from the immersive and interactive training context provided by VR, with a possibility of transferring the skills learnt from therapy to everyday life contexts. The application of VR in aphasia therapy is relatively new. A systematic review and meta-analysis [ 15 ] based on five RCTs/quasi-RCTs concluded that VR-based interventions had a marginally positive clinical effect on aphasia severity compared to conventional treatment, but showed no significant impact on functional communication, repetition, or naming. However, only three of the studies [ 16 – 18 ] adopted a functional approach to treatment, and outcomes for functional communication were reported in Marshall et al. [ 16 ] and Grechuta et al. [ 17 ]. Some studies [ 17 , 19 ] employed different treatment protocols and content across VR and non-VR therapy, making it difficult to isolate VR’s specific contribution. Besides, semi-immersive VR was used in most studies except in Zhang et al. [ 19 ], where immersive VR was applied. Despite the mixed findings, a more recent review [ 20 ] suggested that VR offers a unique opportunity to address rehabilitation at the impairment, activity, and participation levels. We also argue that a more rigorous methodology, i.e., an RCT that uses the same treatment content delivered in VR vs. a non-VR-based intervention, would allow us to compare the crucial features of VR, i.e., immersion and interactivity, in aphasia intervention. Aims and hypotheses to be tested The proposed study aims to examine whether VR-based computerized script training may improve verbal functional communication in PWA and, more importantly, whether such therapy may enhance aphasia treatment outcomes. Immersive VR with 360-degree panoramic scenes, a lower-cost option than three-dimensional modeled applications yet effective at creating a sense of presence [ 21 ], will be delivered via a head-mounted display (HMD). The use of immersive VR is supported by evidence suggesting that greater immersion may better promote treatment outcomes in stroke patients receiving motor rehabilitation (see a review and meta-analysis by Palacious-Navarro & Hogan [ 22 ]) and in social skills learning in some individuals with autism spectrum disorder [ 23 ]. Script training, a functional approach to aphasia rehabilitation [ 24 ], will be chosen due to several reasons. Firstly, it is an evidence-based intervention (see Hubbard et al. [ 25 ] for a review) for fluent and non-fluent PWA. Monologic or dialogic scripts are functional to the daily needs of PWA, e.g., ordering dishes at a restaurant or making a doctor’s appointment, can be prepared and practiced following a cueing hierarchy predefined in the computer program to avoid clinician-led variability in style and thus ensure higher adherence to the treatment protocol. Secondly, the immersion and interactivity provided by VR align perfectly with the theoretical underpinnings and the context-bound nature of script training. The instance theory of automatization [ 26 ] explains that script acquisition (i.e., automatic retrieval of script content) is achieved via retrieving memories of complete, context-bound, and skilled performance through repeated exposure to and practice on the same task [ 27 ]. The immersive experience delivered via an HMD, together with interactions between the PWA and the virtual conversation partner in the interactive videos, will help create a naturalistic and complete context for the PWA to practice the script and eventually achieve automatic retrieval in everyday communication. Last but not least, VR-based therapy allows PWA who may have limited access to multiple locations due to physical constraints and reduced confidence in communication post-stroke to practice the scripts in a safe, repetitive, but less embarrassing manner. Such an unparalleled experience, when compared to the conventional clinical setting, may further enhance the treatment outcomes of script training. Research questions of the current proposed study (1) Can VR-based computerized script training promote verbal functional communication of Cantonese-speaking PWA? This question will be addressed by comparing participants’ performance in the VR treatment condition with that in the no-treatment control across different timepoints of the study. It is hypothesized that the verbal functional communication of PWA in the VR treatment group will improve, while those in the control group will not show significant changes. (2) Is VR-based computerized script training more efficacious than computerized script training without VR in promoting verbal functional communication of Cantonese-speaking PWA? This question will be addressed by comparing participants’ performance in the VR treatment condition with that in the non-VR condition. Materials and methods Pilot data A pilot study (reference number of the Human Subjects Ethics Application Review System of the Hong Kong Polytechnic University Institutional Review Board: HSEARS20221021003–01) has been conducted to: 1) develop the computerized script training for Cantonese PWA, 2) develop the materials and program for script training via VR, and 3) demonstrate feasibility and preliminary efficacy of computerized script training with/without VR. Based on the pre/post comparison of six PWA who were randomly assigned to receive either VR/non-VR treatment from June to August 2023, large effect sizes were obtained in the primary outcome measure (in terms of percentage of words correctly produced without written cues) in both VR (Cohen’s d = 2.03) and non-VR treatment groups (Cohen’s d = 5.52). For secondary outcomes, generalization was observed in both groups, with Cohen’s d = 1.84 and 6.95 for VR and non-VR groups, respectively. Verbal functional communication, as measured by the Cantonese version of the Amsterdam Nijmegen Everyday Language Test (CANELT) [ 28 ], had demonstrated some improvements in the VR (Cohen’s d = 0.75) and the non-VR group (Cohen’s d = 0.36). Positive changes in the aphasia quotient were observed, with a Cohen’s d of 1.36 and 0.53 in the VR and non-VR groups, respectively. Adherence to treatment protocol was similar in both treatment groups. PWA reported a satisfactory experience with computerized script training and VR exposure, with minimal cybersickness, as reflected by an average comfort level rating of 4.6/5 in the VR group. Despite the seemingly unequal aphasia severity in both groups before treatment (mean AQ of 56.4 and 79.0 in VR and non-VR groups, respectively), clinically meaningful changes were observed in both treatment groups in most of the language and communication measures, while some of the secondary outcome measures in the VR group had larger effect sizes than the non-VR group. In sum, the preliminary results have demonstrated the feasibility of both computerized script training and VR-based script practice proposed by the research team, providing strong support for pursuing the current proposal. Study design A prospective, three-armed, open-label, assessor-blinded, randomized controlled trial will be conducted over 20 weeks. Protocol design and data reporting are aligned with the Consolidated Standards of Reporting Trials Statement (CONSORT) and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) for nonpharmacologic trials [ 29 ]. The treatment protocol (version 1.0, dated July 24, 2024) has been registered in ClinicalTrials.gov ( NCT06722092 ). The experimental design is summarized in the S1 Fig . Ethics statement Ethical approval has been obtained from the Human Subjects Ethics Application Review System of the Hong Kong Polytechnic University Institutional Review Board (reference number: HSEARS2023022800302). Written consent will be sought from the eligible participants in the presence of caregivers. Participants A total of 120 Cantonese-speaking PWA will be recruited from rehabilitation centers, stroke patient support groups in Hong Kong, and speech therapy clinics at a local institute. The sample size estimate is conducted using G* power (version 3.1.9.7) repeated-measure, within-between interaction ANOVA, based on 3 groups, 5 repetitions, power of 95% with α = .003 (adjusted for a total 16 multiple comparisons: 3 between groups (VR vs. control, non-VR vs. control and VR vs. non-VR), 3 between timepoints (pre vs. post, pre vs. mid and post vs. mid) and 10 interaction between groups and timepoints), a medium primary outcome effect size of Cohen’s d = 0.5 ( η p 2 = 0.0588), a 0.5 correlation among repetitive measures, a 0.5 non-sphericity correction and an attrition rate of 20%. A projected 20% attrition rate was incorporated into the power analysis to account for potential loss to follow-up. This estimate is informed by historical data from similar protocols, in which dropout rates of 10–20% occurred due to health fluctuations, logistical barriers (e.g., transit difficulties), or waning participant engagement. Attrition is assumed to be non-differential across study arms, as the anticipated reasons for withdrawal are independent of the specific intervention. We assumed a medium effect size of 0.5 based on the smallest effect size of d = 0.74 obtained from Cherney et al. [ 7 ], a study on computerized script training with a comparable total treatment duration. Inclusion criteria include: 1) a stroke onset of more than six months, with an Aphasia Quotient (AQ) below 96.4, as evaluated by the Cantonese version of Western Aphasia Battery (CAB) [ 30 ], 2) premorbid fluent Cantonese speakers, 3) aged between 30 and 80 years, 4) no reported progressive neurogenic disorders such as dementia or Parkinson’s disease, 5) no motor speech disorders of moderate to severe level, based on a rating of 3 or above in the Therapy Outcome Measure [ 31 , 32 ], 6) normal or corrected-to-normal vision and hearing functions. Exclusion criteria include: 1) presence of neurological disorders, e.g., dementia or motor neuron disease; and 2) non-compliance with a 10-minute VR exposure during screening, such as reports of cybersickness or discomfort. Recruitment through the collaborating rehabilitation centers and stroke patient support groups will be done via posters and social media posts. The screening will be done by a trained research postgraduate student/research assistant with a speech-language pathology background. Randomization Co-author DL, who is not involved in participant recruitment, condition assignment, and assessment/ treatment throughout the study, will prepare a central web-based randomization sequence, with an allocation ratio of 1:1:1 to the 1) VR-based treatment condition, 2) non-VR treatment condition, and 3) no-treatment condition. Participant enrolment will be conducted by co-author HTK, and condition assignment will be conducted by author WW and a trained research assistant who is not involved in the enrolment, screening, or assessment of PWA. Simple randomization will be used. PWA who have given informed consent will be randomly allocated to one of the above-mentioned conditions. All participants in the no-treatment group will receive VR/non-VR-based treatment upon the completion of all assessments. Assessment and treatment schedule Participants will receive pre-treatment assessments twice, i.e., at three and one weeks pre-treatment, as baseline. The same set of assessment tasks will be administered mid-treatment, within a week post-treatment, and 8 weeks post-treatment as maintenance. The treatment schedule will be the same for both treatment conditions: 14 therapy sessions will occur twice per week from week 5 to week 7 and from week 9 to week 11. Outcome measures and procedures Primary outcomes: During an assessment session, the PWA’s accuracy and time needed to produce the trained scripts (i.e., treatment probe) in read-aloud and no-cue conditions will be recorded via the computerized script training software. Similar to the training session, the virtual therapist will initiate the conversation, followed by PWA’s response. The no-cue condition will be executed first, followed by the read-aloud condition. The number of sessions required to reach the performance criterion (i.e., 90% accuracy in two consecutive sessions) will also be considered to reflect PWA’s progress. Secondary outcomes: To evaluate treatment generalization, the assessment session will include novel scripts that were not trained but share similar contexts with the trained scripts. Examples include ordering dishes that differ from the trained items or eliciting untrained personal information during a self-introduction. In accordance with the Research Outcome Measurement in Aphasia (ROMA) [ 33 ], the aphasia quotient of CAB [ 30 ], is included as an outcome measure instrument (OMI) for language ability. Since a Hong Kong-adapted version of The Scenario Test [ 34 ] is not available, CANELT [ 28 ], a standardized OMI adapted from the Amsterdam-Nijmegen Everyday Language Test (ANELT) [ 35 ] for Cantonese speakers in Hong Kong, will be included as secondary outcomes in language and communication. CAB [ 30 ] is a standardized aphasia test for measuring aphasia severity. CANELT [ 28 ] assesses the effectiveness of verbal communication in conversation through 20 culturally appropriate scenarios. In addition, PWA’s self-reported OMI on communication and quality of life will be examined via the Cantonese version of the 20-item Communication Outcome after Stroke (Can-COAST) Scale [ 36 ] translated from its original English version (COAST) [ 37 ]. All assessment tasks and their sources of normative data (if applicable) are summarized in Table 1 . Table 1. List of assessment and outcome measures and sources of normative data. Primary outcome Sources of normative data Percentage accuracy of treatment probe correctly produced in no-cue and read-aloud conditions NA Time to produce the scripts in the treatment probe in no-cue and read-aloud conditions NA Number of sessions to reach performance criteria in session probe NA Secondary outcomes Aphasia quotient of CAB Yiu (1992) [ 30 ] Age-adjusted z scores of CANELT Wong (2024) [ 28 ] Total scores of Can-COAST Wong and Kwok (2025) [ 36 ] Generalization Percentage accuracy of generalization probe correctly produced NA Time to produce the scripts in the generalization probe NA Open in a new tab CAB, Cantonese version of the Western Aphasia Battery; CANELT, Cantonese version of the Amsterdam-Nijmegen Everyday Language Test; Can-COAST, Cantonese version of the Communication Outcome after Stroke Scale. NA, Not applicable. Assessment will be done by a trained research postgraduate student with healthcare background, such as speech therapy or rehabilitation science, who is blinded from the therapy condition of subjects. S/he will not be involved in the intervention process. A standardized procedure with audio recording for outcome assessment will be enforced. Primary outcomes and generalization probes are computerized and audio-recorded to minimize and monitor any assessor’s bias. Since blinding participants may be deemed impossible, both the assessor and the PWA are reminded not to mention or discuss the therapy condition assignment during assessment sessions. Treatment materials and procedures A total of 14 individual treatment sessions, given twice/three times per week, will be delivered to both treatment groups. Each session will include a 30-minute computerized script training, followed by a 30-minute practical section delivered with or without VR. No intervention will be given to the no-treatment control group during the study period. However, PWA in the control group will receive either VR or non-VR-based script training for free upon study completion. All treatment sessions will be done in a quiet room in the speech therapy unit by a trained research postgraduate student/research assistant with a speech-language pathology, linguistics, or rehabilitation science background. Since the treatment providers cannot be blinded to treatment condition assessment, the following procedures will be adopted to mitigate their potential expectancy effects: 1) treatment providers will receive standardized training prior to therapy delivery, based on a standardized protocol and therapy manual developed by the authors (WW and HTK). Scripted instructions and feedback will be given. Competency evaluation will be conducted through role-play before intervention delivery; 2) all treatment materials and procedures are standardized and computerized. All training logs and verbal productions during therapy sessions are recorded digitally for monitoring. Treatment providers will fill out a log sheet for each session for recording incidents when protocol is not followed, which will be submitted the principal investigator of the project within the same day, 3) the performance of the treatment providers will be monitored by author (WW) and an independent speech therapist not involved in the study for fidelity checking (see Section ‘Reliability and treatment fidelity’). The principal investigator and the project team will discuss corrective actions for protocol deviations. Script development and selection Six to eight dialogic scripts were developed via pilot study, each script containing five conversational turns, will be used for training (i.e., treatment probe). Each PWA will be interviewed to identify the scripts most relevant and functional for their daily needs. The number of syllables and grammatical complexity in the scripts will be balanced across participants. Computerized script training A computerized script training program delivered in Cantonese will be used with procedures adapted from Cherney et al. [ 27 ]. The first author has already developed the program supported by an internal grant provided by the institute. Each treatment session begins with a session probe, which monitors the PWA’s performance on scripts trained in previous sessions without support/cueing. If the performance on a certain script exceeds 90% in two consecutive sessions, a new script will be introduced. Treatment follows the sequence of 1) The whole conversation script will be presented on a computer screen and read aloud by the virtual clinician, 2) The PWA will read each conversational turn assigned twice in unison with the virtual therapist. 3) The PWA will read aloud the sentence independently while the program will record the verbal response, 4) Treatment proceeds to another conversational turn. Each script will be repeated twice while two to three scripts will be trained in each session in random order. A clinical assistant will be present to monitor and provide technical support. Following the computerized script training, the same sets of scripts will subsequently be practiced for 30 minutes, either in the VR or non-VR condition. The same set of procedures will be applied in the two treatment conditions; they only differ in terms of how treatment materials are presented. VR-based script training The PWA will wear an HMD device for 30 minutes. Interactive 360-degree videos depicting various daily scenarios will be presented. The immersive experience provided by the 360-degree videos will include a visual exploration of the scenario/surroundings (e.g., walking around in a fashion shop/reading a food menu in a restaurant) and audio input via stereo speakers provided by the HMD (traffic on the street, background noise of a Chinese restaurant, etc.). Interactive components will be achieved mainly via communication with the virtual communication partner and its induced events. For example, a waiter in the restaurant will initiate a conversation. The PWA will be given time to respond. If a correct response is produced, the virtual communication partner will ‘interact’ with the PWA by initiating the next conversational turn, and, if applicable, nonverbal reactions/rewards such as presenting the object requested to the PWA. For incomplete or erroneous productions, PWA will be required to repeat the correct response in unison with the conversational partner. The clinical assistant, who accompanies the PWA in the entire training session, will decide and control the type of feedback. Rests within the session will be given, and any possible adverse effects will be monitored and reported. Script training without VR The training flow in the non-VR condition is identical to the VR condition, except that only static photos depicting the scenarios and pre-recorded conversational turns will be presented to the PWA on a computer screen. Data analysis Assessment will be administered by trained research personnel with speech-language pathology background, and therapy will be delivered by trained research assistants or speech-language pathology students who are blinded to the assignment to the treatment condition. Transcriptions will be performed by trained research assistants with backgrounds in linguistics or speech-language pathology. Scoring will be done by the fifth author (HTK), trained speech-language pathology students, and trained personnel with a speech-language pathology or linguistics background. Protocols and guidelines for transcription and scoring will be regularly reviewed by the first (WW) and fifth (HTK) authors. Data analyses will be carried out by the first (WW) and fifth (HTK) authors. Treatment and generalization probes will be scored by i) the percentage of target syllables correctly produced and ii) the Naming and Oral Reading for Language in Aphasia 6-point scale (NORLA-6) with some adaptations. NORLA-6 has been validated [ 38 ] and adopted in a number of script training studies [ 7 , 39 ]. Syllable accuracy will be measured by strict alignment with the personalized script. Partial utterances, as well as semantic and phonemic paraphasia, will be evaluated under the NORLA-6 scale criteria.. Table 2 shows the adapted scoring criteria of NORLA-6. Each word produced by the participant will be given a score from zero to five based on fluency, accuracy, and the nature of errors produced. Adaptations were made to the scoring criteria for Scores 3 and 4; specifically, two conditions will be removed as Cantonese lacks inflectional verb tense and prosodic variation (e.g., stress on incorrect syllable). The remaining scoring criteria will adhere to the NORLA-6 framework to ensure consistency. For instance, the best production will be scored when multiple attempts are made. Commentary productions that are not intended for the target word will not be scored. The efficiency of script production in terms of words produced per minute will also be calculated. The timing window will begin at the completion of the prompt to the participant’s vocal offset. Table 2. Adapted naming and oral reading for language in Aphasia 6-Point Scale (NORLA-6). 5 Accurate and immediate response 4 Accurate but delayed response (A delay is defined as: a pause, with or without fillers, preceding the target word that is atypical of the participant’s oral reading and naming performance. Some participants may show consistent, delayed responses in the context of slow and effortful oral reading and naming. In such cases, all words are rated a 4.) Self-corrected response Minor distortion of a recognizable phoneme Prosodic variation (e.g., stress on incorrect syllable) Correct word produced in the wrong order in the sentence 3 Omission, addition, or substitution of a grammatical morpheme Omission, addition, or substitution of a single phoneme (regardless of the length of the word) Incorrect use of verb tense for irregular verbs 2 Related verbal paraphasia (includes in-class substitutions of function words such as determiners, prepositions, pronouns) Verbal paraphasia with a minor phonemic error Phonemic paraphasia in which more than half of the word is correct 1 Unrelated verbal paraphasia as a substitution for the target word Unrelated response as a substitution for the target word Unintelligible response as a substitution for the target word Phonemic paraphasia in which half or less of the word is correct 0 No verbal response Open in a new tab For secondary outcomes, PWA’s performance on CANELT [ 28 ] will be transformed into z -scores based on the normative dataset collected from 100 healthy Cantonese speakers aged between 30 and 79 years. Meanwhile, raw scores of CAB [ 30 ] and Can-COAST [ 36 ] will be used. Descriptive statistics will first be computed for all outcome measures and PWA characteristics. To examine whether baseline performance is stable across the two pre-treatment assessments, we will use repeated-measure ANOVA to test whether the scores at the two pre-treatment timepoints are comparable across all outcomes. Outcomes with comparable baseline performance will be averaged across the two timepoints for subsequent analyses; conversely, the timepoint with better performance will be treated as baseline for subsequent analyses. Separate linear mixed effect (LME) models with identity link function will be used to investigate whether the use of VR on script training (i.e., experimental conditions) enhances each of the primary and secondary outcomes across timepoint. In each model, experimental conditions, timepoints (categorical variable with three levels – pre-, mid- and post-treatment – to allow for the detection of non-linear treatment effects and to facilitate pairwise comparisons between specific assessment sessions) and their interactions will be fixed factor and one primary/secondary outcome will be used as the dependent variables. Covariates that may interfere with the outcomes, including age, aphasia severity, baseline performance, and education, will be included as fixed factors in the LME models, while random intercept for participant and stimulus item (if appropriate) will also be included in the LME models. In sum, the following statistical models will be used to investigate the treatment outcomes: Primary outcomes: (1) Percentage accuracy of treatment probe in the no-cue condition ~ 1 + timepoint*condition + baseline performance + age + education + baseline CAB score + (1│subject)+ (1│stimulus item) (2) Percentage accuracy of treatment probe in the read-aloud condition ~ 1 + timepoint*condition + baseline performance + age + education + baseline CAB score + (1│subject) + (1│stimulus item) (3) Total time to produce the scripts in the treatment probe in the no-cue condition ~ 1 + timepoint*condition + baseline performance + age + education + baseline CAB score + (1│subject) + (1│stimulus item) (4) Total time to produce the scripts in the treatment probe in the read-aloud condition ~ 1 + timepoint*condition + baseline performance + age + education + baseline CAB score + (1│subject) + (1│stimulus item) (5) Number of sessions required to reach the performance criterion in probing session ~ 1 + timepoint*condition + baseline performance + age + education + baseline CAB score + (1│subject) + (1│stimulus item) Secondary outcomes: (6) CAB ~ 1 + timepoint*condition + baseline performance + age + education + (1│subject) (7) CANELT ~ 1 + timepoint*condition + baseline performance + age + education + baseline CAB score + (1│subject) (8) Can-COAST ~ 1 + timepoint*condition + baseline performance + age + education + baseline CAB score + (1│subject) Generalization. (9) Percentage accuracy of generalization probe ~ 1 + timepoint*condition + baseline performance + age + education + baseline CAB score + (1│subject) + (1│stimulus item) (10) Total time to produce the generalization scripts ~ 1 + timepoint*condition + baseline performance + age + education + baseline CAB score + (1│subject) + (1│stimulus item) The variance inflation factor (VIF) values in the mixed models will be used to examine multicollinearity of the predictors. If the VIF values are large (≥ 10), those highly correlated predictors will be combined into a composite before entering the mixed models. Subjects with incomplete longitudinal data will be retained in the LME model analysis as the LME model estimation using maximum likelihood handles missingness at random well. Any significant results obtained in the above-mentioned LME models will be followed by post-hoc comparisons with Bonferroni correction. Such planned subgroup analyses will be exploratory, aiming to investigate outcomes across different conditions. Model assumptions will be assessed by visualizing the distribution of residuals using Q-Q plots to evaluate normality and scatterplots of predicted versus residual values to check for homoscedasticity. Model fit will be quantified using Marginal/Conditional R 2 values. In the event of significant violations of these assumptions, either appropriate data transformations (e.g., log-transformation) will be applied to the corresponding dependent variable or an alternative link function (e.g., logit link function) will be applied to the corresponding LME models to ensure the validity of the statistical inferences. Sensitivity analyses applicable in the current study, based on Thabane et al. [ 40 ] will include 1) assessment of outliers by z-score or boxplot, and subsequent analysis with/without outliers, 2) re-analyzing the dataset with only cases with complete testing across the timepoints, 3) perform analysis to assess the robustness of our findings across subject recruitment sites by including/excluding the ‘Recruitment Center’ factor in the models, 4) analysis with/without adjustment for baseline characteristics (age, education, baseline CAB and baseline performance of the predicted variables), and 5) use of non-parametric methods (e.g., generalized linear models) vs. LME models to examine the robustness of the findings. Safety considerations Exposure to VR is generally considered to have a low risk profile. Nevertheless, precautionary measures will be implemented to optimize the participant’s safety and acceptability. In the screening session, each participant will have a 10-minute VR script training exposure in which s/he will experience visual/auditory input and engage in conversations/actions similar to those used in the therapy sessions. Those incompatible with the VR script training exposure will be excluded from the study. In each therapy session, PWA will receive a 5-minute break every 10-minute VR exposure. Therapy providers will monitor participants’ conditions closely. A log sheet for reporting adverse events. The protocol for safety monitoring and adverse events reporting will follow the guidelines issued by the Institutional Review Board of the Hong Kong Polytechnic University, based on the National Institute on Aging Adverse Event and Serious Adverse Event Guidelines [ 41 ]. Any discomfort, such as cybersickness, headache, dizziness, or emotional distress induced by VR exposure, will be evaluated using the SSQ during the session, while the incidence will be reported to the principal investigator (WW) on the same day. If the weighted total severity score exceeds 10 in more than one session, indicating significant symptoms, the principal investigator (WW) will lead her research team member (HTK) in discussing study discontinuation with the PWA and their caregiver. PWA can withdraw from the study without any negative consequences. Reliability and treatment fidelity Approximately 20% of the data, randomly sampled across arms, timepoints, and script types, will be blindly scored by the research postgraduate student and an independently trained speech therapist to examine intra- and inter-rater reliability using intraclass correlations. The acceptable reliability threshold will be 90% for both measures. If the reliability measures fall below the target, the principal investigator (WW) and co-author HTK will re-evaluate the scoring criteria and procedures with the research personnel involved in scoring and rescore the data concerned. Treatment fidelity will be monitored by the first author and an independent speech therapist with at least 3 years of experience in aphasia management, using an intervention fidelity checklist based on recommendations by the National Institute of Health Behavior Change Consortium [ 42 ]. Fidelity audits will be implemented every three months by the research team. Study limitations The current study will recruit only Cantonese-speaking PWA; the generalizability of the study findings to speakers of other languages or Chinese dialects should be interpreted with caution. Additionally, during the screening process, PWA who cannot tolerate the 10-minute VR exposure will be excluded from the study. Such selection bias may affect the generalizability of the research findings to broader PWA populations. Timeline of the study Participants will be recruited from 1 st August 2025–31 st December 2026. Assessment and treatment will span from September 2025 to May 2027. Data analysis and dissemination are scheduled to take place between June 2027 and December 2027. Data management plan Data management will be overseen by the Principal Investigator (the first author) and co-authors. This process complies with the requirements of the Institutional Review Board of the Hong Kong Polytechnic University and is independent of the funder. Physical records will be secured within locked file cabinets, with access strictly limited to the research team members. Digital materials, specifically audio recordings, will be stored on secure servers provided by the Hong Kong Polytechnic University and will be accessible only to the research team members. Any data shared on an open-access repository will first undergo de-identification using a unique subject code to preserve anonymity before distribution. Furthermore, any instance of unauthorized data access will be reported to the Institutional Review Board of the Hong Kong Polytechnic University. Dissemination plan The research findings will be disseminated upon the conclusion of data collection and preliminary data analysis, estimated to occur within a four- to six- month timeframe. Initial results will be presented at local and overseas conferences on topics such as speech-language therapy, aphasia intervention and management, and the use of VR and other advanced technologies in rehabilitation. The Principal Investigator (WW) will assume leadership in preparing comprehensive reports and collaborating with co-authors to submit the findings to international peer-reviewed journals approximately six months after the final data analysis. Furthermore, face-to-face and/or online workshops introducing VR Script training, including its technical requirements, setup, and clinical efficacy, will be conducted for healthcare professionals and caregivers supporting aphasia rehabilitation in Hong Kong and neighboring cities. The anonymized dataset will be made accessible via an open-access data repository. Supporting information S1 File. SPIRIT Checklist. (PDF) pone.0350390.s001.pdf (130.2KB, pdf) S1 Fig. SPIRIT Schedule of enrollment, interventions, and assessments. (TIF) pone.0350390.s002.tif (216.4KB, tif) S1 Protocol. Protocol 1.0. (PDF) pone.0350390.s003.pdf (165.9KB, pdf) Acknowledgments We are grateful to the following organizations for their support in participant recruitment in the project: AKA Social Service, The Hong Kong Polytechnic University Speech Therapy Unit, The Hong Kong Stroke Association, The Neighbourhood Advice-action Council NT West Community Rehabilitation Day Centre. Data Availability No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. Funding Statement Wong received the General Research Fund from Hong Kong Research Grants Council for the project (Project number: 15602024). https://www.ugc.edu.hk/eng/rgc/funding_opport/grf/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. References 1. Dijkerman HC, Wood VA, Hewer RL. Long-term outcome after discharge from a stroke rehabilitation unit. J R Coll Physicians Lond. 1996;30(6):538–46. doi: 10.1016/s0035-8819(25)00309-5 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 2. Code C, Herrmann M. The relevance of emotional and psychosocial factors in aphasia to rehabilitation. Neuropsychol Rehabil. 2003;13(1–2):109–32. doi: 10.1080/09602010244000291 [ DOI ] [ PubMed ] [ Google Scholar ] 3. 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Health Psychol. 2004;23(5):443–51. doi: 10.1037/0278-6133.23.5.443 [ DOI ] [ PubMed ] [ Google Scholar ] PLoS One. doi: 10.1371/journal.pone.0350390.r001 Decision Letter 0 Jan Cwik Author information Copyright and License information Roles Jan Cwik : Academic Editor © 2026 Jan Cwik This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMC Copyright notice 10 Feb 2026 -->PONE-D-25-53607-->-->Can immersive virtual reality magnify treatment outcomes of computerized script training on Cantonese speakers with chronic aphasia? Protocol of a randomized controlled trial-->-->PLOS One Dear Dr. Wong, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== Dear Authors, Thank you for submitting your manuscript entitled “Can immersive virtual reality magnify treatment outcomes of computerized script training on Cantonese speakers with chronic aphasia? Protocol of a randomized controlled trial” (PONE-D-25-53607) to PLOS ONE. Your manuscript has now been reviewed by three independent reviewers. All reviewers agree that the study addresses an important and timely clinical question and that the overall randomized controlled design is appropriate. The trial is well motivated, registered, and supported by ethical approval, and the focus on Cantonese-speaking people with aphasia addresses an underrepresented population in the literature. However, while Reviewers 1 and 2 raise primarily clarificatory and reporting-related issues, Reviewer 3 identifies several substantive methodological and procedural concerns that require resolution before the protocol can be considered suitable for publication. After careful consideration of all reviews, I have therefore decided that the manuscript requires Major Revision. Below, I summarise the key issues that must be addressed in a revised version. Major issues requiring attention Randomization and allocation concealment The protocol must provide a clear and explicit description of allocation concealment procedures, including who generates the randomization sequence, who enrolls participants, and who assigns interventions. Please also clarify whether stratified or minimization procedures will be used to balance key prognostic variables across the three arms, or justify why this is not planned. Primary outcome definition and scoring procedures The primary outcome requires more precise operationalization. Please clarify criteria for correct script production, handling of partial responses, self-corrections, and semantic substitutions. In addition, scoring procedures must be specified in greater detail, including the number of raters, blinding procedures, rater training, adjudication rules, and justification or validation of the adapted scoring approach (e.g., NORLA-6 adaptation). Reliability and double scoring The current plan for double scoring a limited proportion of recordings requires strengthening. Please increase and pre-specify the proportion of recordings to be double scored, define acceptable reliability thresholds, and outline procedures if reliability falls below target. Sample size calculation and assumptions Please provide a fully transparent account of the sample size calculation, including justification for the assumed effect size, statistical test framework (e.g., LME vs. repeated-measures ANOVA), assumptions regarding correlations among repeated measures, and how power relates to specific planned comparisons. Attrition assumptions should also be clarified. Statistical analysis plan (pre-specification) The statistical analysis plan requires further pre-specification, including the planned mixed-effects model structure, handling of baseline measures and covariates, treatment of missing data, sensitivity analyses, and approach to multiple comparisons. Planned subgroup or moderator analyses should be clearly identified as confirmatory or exploratory. Blinding and bias mitigation Please clarify how assessor blinding will be maintained and monitored, and how potential expectancy effects related to unblinded treatment providers will be mitigated. Treatment fidelity and therapist training Additional details are required regarding therapist training, treatment manuals, fidelity monitoring procedures, and corrective actions for protocol deviations. Safety monitoring and adverse events The protocol should specify procedures for monitoring and reporting adverse events (including VR-related symptoms), criteria for discontinuation, and the structure of safety oversight (e.g., DSMB or equivalent justification). Eligibility criteria and generalizability Please clarify inclusion and exclusion criteria (including aphasia severity and motor speech disorders) and discuss how VR tolerance-based exclusions may affect generalizability. Additional comments In addition to the major points above, please address the minor and editorial comments from all reviewers, including clarifying timelines, outcome measurement details, data-sharing plans, adherence to reporting guidelines (e.g., SPIRIT), and language clarity. Revision instructions Please submit a detailed, point-by-point response to all reviewer comments, clearly indicating how each issue has been addressed. Revised text should be clearly identifiable. Please note that failure to adequately address the major methodological and procedural concerns outlined above may preclude further consideration of the manuscript. We appreciate the potential contribution of this protocol and look forward to receiving a carefully revised version. Sincerely, Jan Christopher Cwik ============================== Please submit your revised manuscript by Mar 27 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:--> A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. 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The PLOS ONE style templates can be found at -->--> https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and -->--> https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf -->--> -->-->2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. -->--> -->-->When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.-->--> -->-->3. Thank you for stating the following in the Acknowledgments Section of your manuscript: -->-->We are grateful to the following organizations for their support in subject recruitment in the funding application: AKA Social Service, The Hong Kong Polytechnic University Speech Therapy Unit, The Hong Kong Stroke Association, The Neighbourhood Advice-action Council NT West Community Rehabilitation Day Centre.-->--> -->-->We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. -->-->Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: -->-->Wong received the General Research Fund from Hong Kong Research Grants Council for the project (Project number: 15602024).-->--> https://www.ugc.edu.hk/eng/rgc/funding_opport/grf/ -->-->The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript -->--> -->-->Please include your amended statements within your cover letter; we will change the online submission form on your behalf.-->--> -->-->4. Please note that your Data Availability Statement is currently missing the repository name and/or the DOI/accession number of each dataset and a direct link to access each database. If your manuscript is accepted for publication, you will be asked to provide these details on a very short timeline. We therefore suggest that you provide this information now, though we will not hold up the peer review process if you are unable.-->--> -->-->5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.-->--> -->-->6. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions--> --> Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.--> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ********** -->2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.--> Reviewer #1: Yes Reviewer #2: Partly Reviewer #3: Partly ********** -->3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.--> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ********** -->4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ********** -->5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.--> Reviewer #1: Yes Reviewer #2: No Reviewer #3: Yes ********** -->6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters)--> Reviewer #1: For sample size calculation, what test was used, t-test? Was a repeated measure method considered? Descriptive statistics can be added to the statistical analysis plan. Was baseline considered as a covariate in the LME? Change from baseline can be used as the dependent variable. P value adjustment needs to be clearly written. Reviewer #2: The study is well-grounded, and the authors demonstrate a solid understanding of the subject matter and relevant literature. The work addresses an important need to strengthen the validity of studies conducted using virtual reality (VR). However, several points warrant reconsideration: Protocol Design and Covariates: The study design does not account for covariates such as age, severity, and time since stroke, and the power calculation was performed without considering these factors. Additionally, these covariates are not planned to be balanced between groups. This represents a significant limitation that could reduce the validity of the results. Population Specificity: The study focuses on Cantonese-speaking participants. While this is appropriate from a study design perspective, it should be clearly acknowledged as a limitation in the manuscript. Subjective Assessments: Some subjective evaluations are conducted by a single author. It may be advisable for multiple evaluators to perform these assessments independently, followed by a joint review of scores, to improve reliability. General Writing and Clarity: The manuscript has issues with overall fluency, and certain sections contain grammatical errors. A thorough revision of the text is recommended to improve readability and clarity. Overall, the study has strong potential, but addressing the points above would enhance its rigor and the clarity of its presentation. Reviewer #3: - Well-motivated, timely three-arm RCT (VR vs non-VR computerized script training vs no-treatment) targeting an important clinical question for Cantonese-speaking PWA. Trial is registered ( NCT06722092 ), ethics approved (PolyU IRB), and data/code sharing on OSF is declared. The basic design and choice of script training are appropriate; however, several methodological, safety, and analysis details require clarification or strengthening before the protocol is acceptable. Major issues (expanded) 1. Randomization and allocation concealment - Provide explicit allocation concealment procedures: who generates and stores the sequence, who enrolls participants, and who performs assignments. Describe physical/technical safeguards (e.g., opaque sealed envelopes, central web-based randomization). - Consider stratified randomization or minimization on key prognostic variables (baseline AQ/aphasia severity, time since stroke, age) to prevent imbalance across three arms. 2. Primary outcome definition, scoring, and rater procedures - Fully operationalize the primary outcome: precise criteria for “correct” script production (treatment of semantic substitutions, paraphasias, partial utterances, prompts), timing window, and handling of self-corrections. - Provide details on scoring procedures: blinded independent raters, number of raters per recording, training, and adjudication rules. - The NORLA-6 adaptation and counting “semantically acceptable” productions as correct require justification or validation evidence (pilot reliability/validity). If novel, include plan to validate scoring (inter-rater reliability targets, pilot ICCs). 3. Reliability and proportion of double scoring - Ten percent double-scoring is low. Increase to at least 20–25% of recordings, sampled across arms, timepoints, and script types. Pre-specify acceptable ICC thresholds and procedures if reliability is below threshold (retraining, rescoring). 4. Sample size calculation and assumptions - Report full sample-size inputs: effect size origin and justification for d=0.74, assumed correlation among repeated measures, number of repeated measures, alpha adjustment for multiple pairwise comparisons (if applicable), and statistical test basis (LME vs repeated measures ANOVA). Clarify whether power is for VR vs non-VR, VR vs control, or all comparisons. - Explain how the 20% attrition was applied and whether recruitment targets account for missing-at-random vs differential dropout across arms. 5. Statistical analysis plan (pre-specify) - Provide detailed LME specification: random intercepts and/or slopes, whether time is categorical or continuous, covariance structure, fixed effects (arm, time, arm*time), planned covariates (age, baseline AQ, education) and rationale. - State handling of missing data (ML via LME, multiple imputation), sensitivity analyses, and assumptions to be tested. - Predefine primary contrasts and multiple comparison correction approach (hierarchical testing vs Bonferroni). Specify planned subgroup/moderator analyses (aphasia type, severity) and whether they are exploratory. 6. Blinding and bias mitigation - Describe concrete steps to maintain assessor blinding (separate staff, standardized scripts to avoid revealing arm, blinding checks), and plan to assess and report blinding success. - Clarify that therapy deliverers cannot be blinded and how expectancy effects will be mitigated (standardized instructions, scripted feedback). 7. Treatment fidelity and therapist training - Provide details on manuals, training sessions for therapists/assistants, fidelity checklists, frequency of fidelity audits, and predefined corrective actions if deviations occur. Specify who monitors fidelity (independent reviewer) and their criteria. 8. Safety monitoring and adverse events - Specify adverse-event monitoring procedures: which events are tracked (cybersickness, headache, dizziness, emotional distress), how often assessed, reporting timelines, criteria for temporary/permanent discontinuation, and who adjudicates events. - State whether a DSMB or safety oversight committee will be convened; if not, justify and outline alternative safety oversight. 9. Inclusion/exclusion and generalizability - Excluding anyone intolerant to a 10-minute VR exposure introduces selection bias toward those tolerating VR; discuss implications for generalizability and how findings will be interpreted relative to broader PWA populations. - Clarify lower AQ limit (severe aphasia allowed?) and operational criteria for excluding “moderate to severe” motor speech disorders. Minor issues and reporting suggestions 1. Sample and timeline consistency - Reconcile inconsistent recruitment/start dates (May vs Aug 15, 2025) and provide final clear timeline. Provide updated, high-resolution SPIRIT figure 2. Outcome measurement details - For CANELT z-scores and other transformed measures, specify normative data sources and transformation procedures. - Clarify use of averaged baseline (two pre-treatment assessments) vs single baseline value in analyses. 3. Data sharing and reproducibility - Good to see OSF links. Specify exactly which materials will be shared (de-identified audio, transcripts, scoring sheets, analysis code), timing of release, and de-identification steps for audio files. 4. Reporting and adherence to guidelines - Ensure completed SPIRIT checklist and adherence to CONSORT extension for non-pharmacologic trials and ROMA recommendations are demonstrated in the final protocol. 5. Figure/table quality and minor edits - Improve figure resolution and correct small typographical repetitions in submission metadata. ********** -->7. PLOS authors have the option to publish the peer review history of their article ( what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? 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PLoS One. 2026 Jun 2;21(6):e0350390. doi: 10.1371/journal.pone.0350390.r002 Author response to Decision Letter 1 Article notes Copyright and License information Collection date 2026. PMC Copyright notice 28 Apr 2026 Dear Editor, Response letter to the submission “Can immersive virtual reality magnify treatment outcomes of computerized script training on Cantonese speakers with chronic aphasia? Protocol of a randomized controlled trial” (PONE-D-25-53607 & PONE-D-25-53607R1) Thank you very much to the reviewers and editor for their comments and suggestions. We have considered them seriously and addressed them appropriately. Please find our point-by-point responses below. Should you have any questions, please feel free to let us know. Best, Winsy Wing-Sze Wong (Corresponding author) PONE-D-25-53607R1 Please upload a Response to Reviewers letter which should include a point by point response to each of the points made by the Editor and / or Reviewers. (This should be uploaded as a 'Response to Reviewers' file type.) Response: The Response to Reviewers letter is uploaded to the system. Please upload a copy of Figure 2 Response: The supporting information has been modified in the manuscript. In accordance with PLOS ONE editorial guidelines, the SPIRIT checklist (PDF) and SPIRIT Schedule (TIFF) have been uploaded as S1 Supporting Document and S1 Figure, respectively. Additionally, Protocol 1.0 has been uploaded as S1 Protocol in supporting information. Please note that Figure 2 is not included in the submission. Statement of fig2a is removed from line 303-304. PONE-D-25-53607 Major issues requiring attention 1. Randomization and allocation concealment The protocol must provide a clear and explicit description of allocation concealment procedures, including who generates the randomization sequence, who enrolls participants, and who assigns interventions. Please also clarify whether stratified or minimization procedures will be used to balance key prognostic variables across the three arms, or justify why this is not planned. Response: An explicit description of randomization and allocation concealment had been added under the Participant section (lines 187-204) and Randomization (lines 219-228). We did not plan to balance the prognostic variables (e.g., age, aphasia severity, and lesion size) in the condition assignment due to practicality issues. For instance, most of the stroke patients in Hong Kong did not have MRI scans post-stroke due to resource limitations. It is therefore impossible to consider all these variables during condition allocation. We fully understand their potential impacts on aphasia therapy outcomes; these variables (where available) will be included as covariates in the analysis, illustrated in the LME models (lines 385-443). 2. Primary outcome definition and scoring procedures The primary outcome requires more precise operationalization. Please clarify criteria for correct script production, handling of partial responses, self-corrections, and semantic substitutions. In addition, scoring procedures must be specified in greater detail, including the number of raters, blinding procedures, rater training, adjudication rules, and justification or validation of the adapted scoring approach (e.g., NORLA-6 adaptation). Response: Scoring will be performed by the fifth author, trained speech-language pathology students, and trained personnel with backgrounds in speech-language pathology or linguistics (lines 345-349). Assessors will be blinded to the intervention condition. Patients will be reminded to keep their intervention condition confidential during assessment. Blinding procedures for assessment and treatment are detailed in lines 266-271. Adaptation of NORLA-6 concerns the deletion of rules that are not applicable to Cantonese (including prosodic variation of rating 4 and verb tense use in rating 3; please refer to Table 3 for details). The remaining scoring criteria will be consistent with the NORLA-6 framework. Detailed scoring procedures and criteria are mentioned in lines 345-371. 3. Reliability and double scoring The current plan for double scoring a limited proportion of recordings requires strengthening. Please increase and pre-specify the proportion of recordings to be double scored, define acceptable reliability thresholds, and outline procedures if reliability falls below target. Response: The proportion of recordings to be double-scored has been increased to 20%. The reliability threshold and contingency procedures for low-reliability are detailed in lines 468-471. 4. Sample size calculation and assumptions Please provide a fully transparent account of the sample size calculation, including justification for the assumed effect size, statistical test framework (e.g., LME vs. repeated-measures ANOVA), assumptions regarding correlations among repeated measures, and how power relates to specific planned comparisons. Attrition assumptions should also be clarified. Response: Sample size estimation was conducted using G*Power for repeated measurements, within-between interaction ANOVA. Lines 187-204 detailed the sample size calculations and assumptions, including a clarified rationale for the expected attrition rate. 5. Statistical analysis plan (pre-specification) The statistical analysis plan requires further pre-specification, including the planned mixed-effects model structure, handling of baseline measures and covariates, treatment of missing data, sensitivity analyses, and approach to multiple comparisons. Planned subgroup or moderator analyses should be clearly identified as confirmatory or exploratory. Response: Further details regarding the pre-specification of the statistical analysis, including the planned mixed-effects model structure, handling of baseline measures and covariates, treatment of missing data, sensitivity analyses, and approach to multiple comparisons, have been provided in lines 371-443. Subgroup analyses are exploratory (lines 426-427). 6. Blinding and bias mitigation Please clarify how assessor blinding will be maintained and monitored, and how potential expectancy effects related to unblinded treatment providers will be mitigated. Response: As assessors will be blinded to the intervention condition, patients will be reminded to keep their intervention condition confidential during assessment. Blinding procedures for assessment and treatment are detailed in lines 266-271. Further details regarding bias mitigation have been addressed in lines 281-294. 7. Treatment fidelity and therapist training Additional details are required regarding therapist training, treatment manuals, fidelity monitoring procedures, and corrective actions for protocol deviations. Response: Therapist training and treatment manuals will be monitored and developed by the authors (WW and HTK). Fidelity monitoring will be conducted by the author (WW) and an independent speech therapist, while the PI and the research team will oversee corrective actions for protocol deviations. These procedures have been addressed in lines 281-294 and lines 471-475. 8. Safety monitoring and adverse events The protocol should specify procedures for monitoring and reporting adverse events (including VR-related symptoms), criteria for discontinuation, and the structure of safety oversight (e.g., DSMB or equivalent justification). Response: The project will follow safety guidelines issued by the Institutional Review Board of the Hong Kong Polytechnic University, based on the National Institute on Aging Adverse Event and Serious Adverse Event Guidelines lines 451-457. Specific procedures for adverse event monitoring have been further addressed in lines 457-463. 9. Eligibility criteria and generalizability Please clarify inclusion and exclusion criteria (including aphasia severity and motor speech disorders) and discuss how VR tolerance-based exclusions may affect generalizability. Response: Criteria for defining the severity of aphasia and motor speech disorders are clarified (lines 205-207, 209-210). The study includes PWA with an aphasia quotient below 96.4 and no motor speech disorders of moderate to severe level according to the Therapy Outcome Measurement. The exclusion of PWA unable to tolerate 10 minutes of VR exposure may result in selection bias, which might impact the generalizability of the results. Detailed clarification of the inclusion and exclusion criteria can be found in lines 205-217. We agree that VR-based exclusions may affect generalizability, which has been included as a limitation of the study (lines 479-481). Additional comments In addition to the major points above, please address the minor and editorial comments from all reviewers, including clarifying timelines, outcome measurement details, data-sharing plans, adherence to reporting guidelines (e.g., SPIRIT), and language clarity. Response: The above-mentioned comments have been addressed in response to the reviewer’s feedback (please refer to the specific responses below). Journal Requirements: 1. When submitting your revision, we need you to address these additional requirements. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Response: The manuscript has been edited according to PLOS ONE’s style requirements. 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section. Response: The name of the funder has been corrected in the ‘Funding Information’ section. 3. Thank you for stating the following in the Acknowledgments Section of your manuscript: We are grateful to the following organizations for their support in subject recruitment in the funding application: AKA Social Service, The Hong Kong Polytechnic University Speech Therapy Unit, The Hong Kong Stroke Association, The Neighbourhood Advice-action Council NT West Community Rehabilitation Day Centre. We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: Wong received the General Research Fund from Hong Kong Research Grants Council for the project (Project number: 15602024). https://www.ugc.edu.hk/eng/rgc/funding_opport/grf/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript Please include your amended statements within your cover letter; we will change the online submission form on your behalf. Response: Regarding the Acknowledgments section, we clarify that the mentioned organizations provided support solely for participant recruitment and were not involved in funding acquisition; amendments have been made to lines 511-514. 4. Please note that your Data Availability Statement is currently missing the repository name and/or the DOI/accession number of each dataset and a direct link to access each database. If your manuscript is accepted for publication, you will be asked to provide these details on a very short timeline. We therefore suggest that you provide this information now, though we will not hold up the peer review process if you are unable. Response: The links for the code and data have been added to the Data availability (lines 520-522) and Code availability sections (lines 525-526). 5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. Response: The ethics statement has been relocated to the Methods section in lines 181-185. 6. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. Response: Not applicable. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Reviewer #1: For sample size calculation, what test was used, t-test? Was a repeated measure method considered? Descriptive statistics can be added to the statistical analysis plan. Was baseline considered as a covariate in the LME? Change from baseline can be used as the dependent variable. P value adjustment needs to be clearly written. Response: Sample size estimation was conducted using G*Power (version 3.1.9.7) for repeated measurements, within-between interaction ANOVA. The detailed calculation methodology is provided in lines 187-204. Descriptive statistics for outcome measures and characteristics of PWA have been added under the section of Data Analysis (lines 371-372). We agree that baseline performance should be included in the LME and each model is specified in lines 372-419. P-value adjustment has been clarified (lines 425-426). Reviewer #2: The study is well-grounded, and the authors demonstrate a solid understanding of the subject matter and relevant literature. The work addresses an important need to strengthen the validity of studies conducted using virtual reality (VR). However, several points warrant reconsideration: Protocol Design and Covariates: The study design does not account for covariates such as age, severity, and time since stroke, and the power calculation was performed without considering these factors. Additionally, these covariates are not planned to be balanced between groups. This represents a significant limitation that could reduce the validity of the results. Response: Due to practicality issues, we did not plan to balance the factors in condition allocation. We did not plan to balance the prognostic variables (e.g., age, aphasia severity, and lesion size) in the condition assignment due to practicality issues. For instance, most of the stroke patients in Hong Kong did not have MRI scans post-stroke due to resource limitations. It is therefore impossible to consider all these variables during condition allocation. We fully understand their potential impacts on aphasia therapy outcomes; these variables (where available) will be included as covariates in the analysis, illustrated in the LME models (lines:385-419). Population Specificity: The study focuses on Cantonese-speaking participants. While this is appropriate from a study design perspective, it should be clearly acknowledged as a limitation in the manuscript. Response: We thank the reviewer for raising this. Population specificity has been addressed in the limitation section (lines 477-478). Subjective Assessments: Some subjective evaluations are conducted by a single author. It may be advisable for multiple evaluators to perform these assessments independently, followed by a joint review of scores, to improve reliability. Response: We agree with the reviewer’s suggestions. Scoring and subjective evaluation will be conducted by the fifth author (HTK), trained speech language pathology students and trained personnel with speech language pathology or linguistics background (lines 345-349). General Writing and Clarity: The manuscript has issues with overall fluency, and certain sections contain grammatical errors. A thorough revision of the text is recommended to improve readability and clarity. Response: The manuscript has been proofread by a professional copywriter for editorial clarity. Overall, the study has strong potential, but addressing the points above Attachment Submitted filename: Response_to_Reviewers(PONE-D-25-53607 & PONE-D-25-53607R1).docx pone.0350390.s005.docx (47.9KB, docx) PLoS One. doi: 10.1371/journal.pone.0350390.r003 Decision Letter 1 Jan Cwik Author information Copyright and License information Roles Jan Cwik : Academic Editor © 2026 Jan Cwik This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMC Copyright notice 13 May 2026 Can immersive virtual reality magnify treatment outcomes of computerized script training on Cantonese speakers with chronic aphasia? Protocol of a randomized controlled trial PONE-D-25-53607R1 Dear Dr. Wong, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Jan Christopher Cwik, Prof. Dr. Dr. Academic Editor PLOS One Reviewers' comments: Reviewer's Responses to Questions --> Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.--> Reviewer #1: Yes ********** -->2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.--> Reviewer #1: Yes ********** -->3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.--> Reviewer #1: Yes ********** -->4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.--> Reviewer #1: Yes ********** -->5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.--> Reviewer #1: Yes ********** -->6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters)--> Reviewer #1: All my concerns are addressed. ********** -->7. PLOS authors have the option to publish the peer review history of their article ( what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .--> Reviewer #1: No ********** PLoS One. doi: 10.1371/journal.pone.0350390.r004 Acceptance letter Jan Cwik Author information Copyright and License information Roles Jan Cwik : Academic Editor © 2026 Jan Cwik This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMC Copyright notice PONE-D-25-53607R1 PLOS One Dear Dr. Wong, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing . If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Dr. Dr. Jan Christopher Cwik Academic Editor PLOS One Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Supplementary Materials S1 File. SPIRIT Checklist. (PDF) pone.0350390.s001.pdf (130.2KB, pdf) S1 Fig. SPIRIT Schedule of enrollment, interventions, and assessments. (TIF) pone.0350390.s002.tif (216.4KB, tif) S1 Protocol. Protocol 1.0. (PDF) pone.0350390.s003.pdf (165.9KB, pdf) Attachment Submitted filename: Response_to_Reviewers(PONE-D-25-53607 & PONE-D-25-53607R1).docx pone.0350390.s005.docx (47.9KB, docx) Data Availability Statement No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. Articles from PLOS One are provided here courtesy of PLOS ACTIONS View on publisher site PDF (409.2 KB) Cite Collections Permalink RESOURCES Similar articles Cited by other articles Links to NCBI Databases Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov Back to Top

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