Exploration of Neuroprotective Therapy

Table 2. Characteristics of included studies.

Author(s), publication year; country	Sample	Participants (n); mean age and SD	Study design	HMD technology	Cognitive training	Training duration (days × weeks × minutes)	Outcome measure	Main results	Notes
Park et al. [38], 2020; Republic of Korea	Amnestic MCI	Fully IVR (n = 10); 71.80 ± 6.61 Control group (n = 11); 69.45 ± 7.45	RCT	HTC Vive, VR controllers	Memory, executive function, processing speed, attention	2 d × 12 w × 30 min	K-MMSE Korean Colour-Word Stroop Test SGDS-K	Within-group analysis did not indicate any significant change after 12 weeks.	Control group participants continued their normal activities. No clear theoretical framework or model was reported as the rationale for the intervention. The authors proposed some explanations for the non-significant results: 1) The relatively short intervention duration compared to studies with longer training periods (e.g., 6 months), 2) the intervention did not include physical exercise components, which the authors suggest may be critical for dementia prevention. Reported methodological limitation: small sample size.
Zhu et al. [39], 2022; China	MCI & MD	MCI (n = 18); 82.94 ± 6.44 MD (n = 13); 85.76 ± 4.67	Pretest-posttest study design	HTC Vive Pro Eye, VR controllers	Memory, attention, executive function, calculation ability	3 d × 5 w × 20–30 min	MMSE & MoCA AVLT STT SDMT	Within-group analysis indicated significant change after 5 weeks for both MCI and MD groups.	No control group was included in the study. No specific theory was used to explain the reported cognitive outcomes. However, the neural mismatch model was referenced to explain participants’ discomfort experienced in the fully IVR environment. The authors suggested that increasing exposure time during the session may help reduce discomfort and improve user adaptation. Reported methodological limitation: small sample size, lack of active comparison groups.
Zając-Lamparska et al. [40], 2019; Poland	MD	MD (n = 27); 72.04 ± 7.43 Healthy adults (n = 72); 67.86 ± 5.83	Pretest-posttest study design	Oculus Rift DK2, Xbox 6DOF control pad	Attention, memory, language, and visuospatial processing	2 d × 4 w × 45 min	Attention Memory, language Visuospatial processing	Within-group analysis indicated some significant change after 4 weeks of fully IVR intervention for the MD group. There were some non-significant cognitive measures.	No control group was included for this fully IVR intervention. The cognitive training games used in the study were not described in full detail; however, a brief description of GRADYS training software is provided in Zając-Lamparska et al. [41]. No specific theoretical framework was used to explain the reported results. Reported methodological limitation: lack of an active comparison group.
Kang et al. [42], 2021; Republic of Korea	Predementia {MCI or Subject cognitive decline}*	Total (n = 41); 74.51 ± 5.81	RCT	Oculus Rift CV1 display, Oculus Touch controllers	Attention, executive function, and memory	2 d × 4 w × 20–30 min	MMSE Attention Language ability Memory Frontal executive function MRI	Within-group analysis indicated a significant change in verbal memory, language, and related functions, and TMT-B for the fully IVR group after 4 weeks of intervention.	A control group was included with participants continuing “business as usual”. The cognitive reserve model was used to provide the rationale for the study. The Van Sommers model was applied to explain improvements observed in the RCFT copy test, based on proposed links between visuospatial construction demands in the fully IVR environments and frontal-occipital functional connectivity. Reported methodological limitation: small sample size, lack of an active comparison group.
Maeng et al. [43], 2021; Republic of Korea	MCI	MCI (n = 31); 73.2 ± 7.3 Healthy adults (n = 25); 71.6 ± 4.4	Not reported	Samsung Odyssey HMD, motion controllers	Memory, attention, executive function	8 sessions × 4 w × 50–60 min	CERAD-K (each cognitive domain)	Within-group analysis indicated significant change in some CERAD-K outcomes (Word list memory, word list recall, word list recognition, constructional recall, TMT-A, Stroop-C, Stroop-CW) after 4 weeks of intervention for the MCI group.	No control group was included in this study. There was no specific theoretical framework or model that was used. However, the authors examined the sense of presence, hypothesising that it would differ from that of cognitively normal individuals; however, no significant difference was found. Reported methodological limitation: small sample size, no follow-up tests.
Yang et al. [44], 2022; Republic of Korea	MCI*	Fully IVR (n = 33); 72.5 ± 5 Exercise (n = 33); 67.9 ± 3.6 Control (n = 33); 72.6 ± 5.6	RCT	Oculus Quest headset, VR controllers	Attention, working memory Sourced from Thapa et al. [30] (2020)	3 d × 8 w × 100 min	MMSE TMT-A SDST NCGG-FAT	Within-group analysis indicated a significant change in global cognitive function (MMSE, TMT-A, and SDST) after 8 weeks of training intervention.	Three comparison groups were included: exercise intervention group, a control group receiving 30-min educational seminars, and a fully IVR group. No specific theory was used to provide a rationale for the study or to explain the cognitive outcomes. However, the authors’ reference to the sense of presence to interpret observed neural-level changes in the brain. Reported methodological limitation: inconsistent intervention frequency, female-dominant sample.
Thapa et al. [30], 2020; Republic of Korea	MCI	Fully IVR (n = 34); 72.6 ± 5.4 Control (n = 34); 72.7 ± 5.6	RCT	Oculus Quest headset, VR controllers	Memory	3 d × 8 w × 100 min	MMSE-DS NCGG-FAT TMT-A TMT-B SDST EEG recording	Within-group analysis indicated a significant change in global cognitive function (TMT-A, TMT-B, SDST) after 8 weeks of training intervention.	A control group was included; participants completed eight sessions of an educational program or general healthcare, delivered once per week, with each session lasting 30–50 min. The intervention group also received educational content. No specific theoretical framework or model was provided for the rationale or to explain the significant findings. Reported methodological limitation: no follow-up test during the intervention.
White and Moussavi [45], 2016; Canada	Individual with the onset stage of AD	74-year-old male	Case study	Oculus Rift DK VRN, wheelchair motion sensors	Spatial navigation	3 d × 7 w × 45 min	MoCA	The participant’s MoCA score increased from 24 to 26 after 7 weeks of training intervention.	The cognitive reserve model was used as the theoretical rationale for the study. The Morris water task was used as a model for IVR-based spatial navigation assessment. The authors suggested that including periodic “booster” sessions to maintain and reinforce any potential improvements in cognitive reserve.

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*: Studies that conducted a power analysis. AVLT: Auditory Verbal Learning Test; CERAD: Consortium to Establish a Registry for Alzheimer’s Disease; EEG: electroencephalogram; HMD: head-mounted display; IVR: immersive virtual reality; MCI: mild cognitive impairment; MD: mild dementia; MMSE: Mini-Mental State Examination; MoCA: Montreal Cognitive Assessment; NCGG-FAT: National Center for Geriatrics and Gerontology Functional Assessment Tool; RCFT: Rey-Osterrieth Complex Figure Test; RCT: randomized controlled trial; SD: standard deviation; SDMT: Symbol Digit Modalities Test; SDST: Symbol Digit Substitution Test; SGDS-K: Short Form Geriatric Depression Scale-Korean version; STT: Shape Trial Test; TMT: Trial-Making Test.

Declarations

Author contributions

EACO: Conceptualization, Methodology, Formal analysis, Investigation, Writing—original draft, Project administration, Writing—review & editing. RK: Methodology, Validation, Writing—review & editing. AP: Methodology, Validation, Writing—review & editing. BTS: Supervision, Validation, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

The datasets supporting the findings of this study are available from the corresponding author upon reasonable request.

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

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