Abstract
Age is recognized as the major factors of dementia, especially in for Alzheimer’s disease (AD). Given to the aged population, the increased number of demented population has been receiving a great impact in our society. Unfortunately, so far, no cured medicines have been demonstrated to provide effective treatment in AD. The combination of pharmacological and non-pharmacological interventions has been proposed to manage dementia with potential benefits especially in decreasing caregiver’s burden and behavior, as well as psychological problems of demented patients. Recently, giving to the glorious development in digital technologies, the virtual reality, one of the non-pharmacological interventions has been used extensively in dementia managements for its strengths which can be adapted in accordance with the heterogeneous needs from demented patients and their caregivers. However, various study designs and other reasons made these results difficult to be interpreted. In this review our goal is to provide a better understanding for these points.
1 Unmet needs for dementia
Age is recognized as the major factors of dementia, especially in for Alzheimer’s disease (AD). Importantly, given to the aging population, the elderly individuals are under the risk of having dementia in the future who will present the progressive deterioration of cognition, impair daily activity and appear behavior and psychological problems, which together will lead to disability and functional impairment of patients themselves. A study has indicated that approximately 40 million people with age over 65 years are suffering from dementia, and 70% of them are estimated having clinically diagnosed AD [1], which mainly resulted from the aging and increased life span. In other words, the improved life quality and medical situation in developing and developed countries will lead to increased life expectancy, and therefore to higher incidence and prevalence of dementia [1, 2]. These demented population will become a huge burden and increase the socio-economical cost soon [1, 3]. Unfortunately, so far, no sufficient disease-modifying and cured treatments have been demonstrated to be effective in the therapies of AD. Acetyl-cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist are currently approved medicines to benefit cognitive and behavioral and psychological outcomes, but their clinical impact and efficacy to all course of dementia still remain controversial [4– 6].
2 Combined interventions for dementia: pharmacological treatment and non-pharmacological intervention
Dementia is disease with various neurode-generative disorders that impairs cognitive functions such as memory, orientation, executive function, language, behaviors and psychological function [1, 7] and eventually will reduce the quality of life (QoL) [7]. With the unconfirmed known pathogenesis of dementia, it is not easy to discover brand-new pharmacological treatments for it. Therefore, current management of dementia has considered how to bring these approaches into modifying those potential risks such as environmental and cardio-vascular risks and providing, adequate behavioral and lifestyle interventions to alter the clinical course [4– 7].
Due to the limited efficacy of current pharmacological treatment, the one-year cognitive response rate is around 50%–60% for acetyl-cholinesterase inhibitors [8, 9], and possibly potential benefits of non-pharmacological intervention (NP-I) to slow the deterioration of AD [10, 11], the combined management of AD to improve patient’s function, and lessen the caregiver’s burden have been proposed [10]. NP-I encompasses a wide range of manipulation from simple cognitive stimulus to complex approaches [12], which are hopefully to adapt the underlying pathophysiological mechanisms and to reduce the disability and caregiver’s burden as long as possible, as the disease progresses, especially in those behavioral and psychological symptoms of dementia (BPSD). As such, there is a trend towards the investigation of nonpharmacological interventions, psychosocial interventions, to enhance the well-being and cognitive function of demented patients [11]. Cognitive and behavior interventions are proposed to reduce the burden of disease to caregiver and care system, especially if introduced during the earlier stage of dementia [12– 14]. These interventions will assist demented patients to remain engaged in preserved cognition and provide cognitive and behavior stimulation in order to prolong independence and increase QoL after their effects of modifying risk factors and increasing cortical stimulations for dementia [15].
3 Behavioral and psychological symptoms of dementia (BPSD)
BPSD, usually well-known along with the progression of dementia, are a group of clinical syndromes resulted from dementia, which was characterized by alterations of perception (hallucinations or misidentification), mood (depression, anxiety, or apathy), thinking (delusion), and behavior (aggression, agitation, disinhibition, irritability, socially or sexually inappropriate behavior, sleep disorder, eating behavior or other queer behavior) [16]. The BPSD has frequently reported across all types of dementia, such as 50%–80% in AD, greater than 80% in frontal-temporal dementia, and 50%–70% in dementia with Lewy body and vascular dementia [17, 18]. The BPSD is the most distressed to caregivers and frequently lead to be institutionalized for patients. BPSD may occur in all stages of AD, and even in patient with a very early stage of dementia such as mild cognitive impairment (MCI). But, our recently published national-wide study showed that the prevalence and severity of BPSD increase with dementia severity, and are more frequent in the moderate stages [19]. In that study investigating a total of 4,722 institutional residents in Taiwan has shown a prevalence of dementia was 87.2% (4,119 of 4,722 residents), out of all residents with dementia, 1,546 (37.5%) of these demented residents used to have BPSD in his past 3 months when recruited for the survey. The most frequent reported BPSD were nighttime behavior (17.9%), resistance against care (13.4%) and depression (12.9%). Older age (p = 0.0146), female (p = 0.0052), and lower Mini-Mental State Examination (MMSE; p = 0.0005) scores were significantly related to BPSD. Moderate stage of dementia (p < 0.0001) and mild activities of daily living (ADL) dependence (p < 0.0001) have higher possibility of having BPSD. Past medical history of orthopedic disease (p = 0.0020), eye disease (p = 0.0001), genitourinary disease (p = 0.0474), dementia (p < 0.0001), psychiatric disorder (p < 0.0001) and intellectual disability (p = 0.0094) were associated with increased risks of having BPSD [19]. Other study also has indicated the environmental factors such as noise, overstimulation, isolation, inadequate temperature, change of routine practice, as well as the characteristics of caregiver were all associated with the BPSD [20, 21]. All these reported factors related to having BPSD, possibly will be becoming the limitations of using virtual reality (VR) intervention for reminiscence, especially in the hearing and vision impairment.
3.1 NP-I to BPSD
There are increasing number of studies addressing the efficacy of NP-I to BPSD recently. The contents of NP-I range from sensory stimulations to psychological and behavioral approaches, and include environmental design, reminiscent intervention, light intervention, aromatherapy, physical massage, music therapy, and pleasant events and activity engagement [22– 24]. These heterogeneous interventions and study designs have made the results inconsistent and not easy to be interpreted although potential benefits has been documented, and the strength of evidence is overall low with great heterogeneity. Factors associated with better responses for these interventions include a preserved underlying cognitive function, less impaired ADL and communication, and relative intact function of speech for communication. Staff barriers and having pain are usually associated with worse outcomes [25] because pain and uncomfortable situation may limit the application and the efficacy for NP-I, and will contribute to BPSD [26, 27]. Besides, reasons accounting for the results majorly coming from various types of intervention, follow-up of study duration, outcome measurements, and where the study has been conducted. If studies addressing BPSD performed in qualified institutes where well-trained health professionals are involved for a better outcome [26]. On contrary, the characteristics of these caregivers will be related to the presentation of BPSD, especially in non-institutionalized demented patients [21] that possibly will make the same interventions, NP-I, to have different outcomes due to the caregiver’s characteristics in recognizing and reporting these BPSD.
3.2 Caregiver’s characteristics to BPSD
Given to the caregiver’s characteristics will contribute to BPSD, which will make the interpretation of effects of NP-I to BPSD difficult. In order to clarify the association between caregiver characteristics and BPSD in demented patients, especially in AD, a cross-sectional study was conducted on 190 AD patients with their 190 matched caregivers in Kaohsiung Municipal Ta-Tung Hospital in Taiwan. BPSD of AD patients was evaluated with Neuropsychiatric Inventory Questionnaire (NPI) [28]. The results have indicated caregiver’s educational level was positively correlated to severity of reporting symptoms of BPSD of patients, hallucinations, agitation/aggression, and apathy/indifference, and will be distressed with agitation/aggression. In case a main or primary caregiver was child (children), children were positively related to the severity of and will be distressed with disinhibition but significantly negative correlation to the severity of anxiety of patient. Differently, if the main or primary caregiver was spouse, spouse was significantly positively related to the severity and will be distressed of anxiety and appetite/eating, but only be distressed by nighttime behaviors of patient. These results have indicated the heterogenous study results of NP-I to BPSD may be related to the potential effects from caregivers, which should be interpreted cautiously.
4 VR in dementia: considerations of patients and caregivers
Before the application of VR technique in cognitive stimuli or rehabilitation, a publication indicated the complicated and heterogenous plasticity of the prefrontal high cortical function which can be enhanced through a custom-designed video game during aging [29]. These reports have highlighted the possibility of cognitive function being interactively and bi-directionally manipulated through external stimulus and internal internalization, and finally to be consolidated.
An image-based rendering technology refers to the computerized reconstruction of a real environment to provide possibly better interaction between testing and tested targets. Such technology will bridge the testing and tested target without interface barrier in which usually happened in routine tests using paper and pencil or questionnaires administrating by a rater. A study examined the same testing material but different deliveries by two-dimensional (2D) prints and wearing three-dimensional (3D) liquid crystal display (LCD) shutter glasses. Those participants reported being more satisfied with the virtual one compared to the previous paper version. Particularly, participants having apathy were more interested and beneficial in the virtual reality situation compared to nonapathetic individuals (p = 0.002) [30].
VR allowed a user to enrich in a 3D digital space generated by computer-related technology and consisting of objects or environment seemingly “real world” without sharing all of their physical features such as volume, weight, smelling, superficial sensation, and temperature [30]. The applications of VR intervention to evaluate and train AD patients have been examined in several studies with remarkable effects [31– 34]. Using VR can reduce the cost to establish or reconstruct the real objects such as buildings or surroundings which cannot be achieved within limited time and space and importantly these events are more easily to be controlled and quantified compared to the real-world issues [35].
In past studies, VR has shown it potentials in training cognitive function for AD patients in various domains including attention [36], executive functions [37], memory [38], orientation [39], and ADL [40]. Recent research is focusing on the comparison whether VR based tests would be more ecological and sensitive to traditional pen-and-paper tests. Due to, however, different interfaces between testing and examined persons in two kinds of test, the real differences, if any, are not easy to be evaluated. In other words, the content and procedures of testing would be modified to fit the necessity of VR based approach when the common pen-and paper examination was transformed into VR testing. Another consideration limiting the use of VR would be a demented patient who cannot complete the VR training or intervention well due to impaired comprehension and executive function, especially in advanced dementia. Whether the caregiver can provide assistance for patient to access this intervention well or complete such testing has been becoming an important issue to make VR have its greatest performance.
4.1 VR as a therapeutic tool
The use of VR to assist the care of demented people was well recognized in recent years [41]. In summary, VR entails presenting the evaluation of clinical outcome for mood, behavior, and cognition completed by quantitative psychometrics administrated to caregivers or patients for an overall assessment. Positive attitude towards using VR were frequently reported among patients and their caregivers, including experiencing more pleasure, more alert to the training, and less apathy in patients [41, 42].
A recent study has proposed an innovative AD screening tests based on virtual environment to evaluate impaired memory function through recalling common objects and recent events, and language changes for these patients [43]. The interactive virtual simulations to represent real situation which was hardly established in routine practice, allowed the user to act in a real-life-like environment for deliberate and interactive learning and being evaluated. Such instruments were also recognized as promising tools to assess patient’s cognition and function [44, 45] and such intervention in some studies have reported will improve patient’s quality of life [46].
4.2 Lasting effects of VR intervention in dementia
Recently, the VR-based memory training has demonstrated effectiveness in improving memory functions in elderly persons having memory deficits through a 6-month randomized controlled study [41]. In that study, the researchers examined the change of cognitive function through VR-based memory training, and have reported such interventions have had significant improvements in case group in their memory function, especially in long-term recall, compared to control group not receiving VR-based memory training. Although these significant findings have been reported previously, the study did not access the lasting effects of VR-based training if the training was removed and that recruited participants were elderly persons with memory deficits, not demented.
What the effects of VR-based training in demented patients were and how long of such effects could last after removing VR training still remain unknown. In order to answer such question, a recent study conducted at Kaohsiung Municipal Ta-Tung hospital is going to answer the question, in which we have investigated the effects of immersive VR-based reminiscent intervention in demented participants and evaluated the neuropsychiatric function with an interval of 3 months after the end of VR-based reminiscent intervention and followed another neuro-psychological evaluation 3 months later after removing the intervention.
20 AD participants, 2 of whom with clinical dementia rating (CDR) 0.5, 15 with CDR 1, and 3 with CDR 2 had completed the study evaluated by MMSE [47], cognitive ability screening instrument (CASI) [48], Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) [49], Center for Epidemiological Studies Depression Scale (CES-D) [50], and Zarit Caregiver Burden Interview (ZBI) [51]. There were no significant differences in the MMSE, CASI and its subdomains, although AD was a progressively degenerative disease, CDR-SB, and ZBI scores in the first interval of 3 months evaluation, while the scores for CES-D significantly decreased from 6.2 ± 5.7 to 3.2 ± 4.3 (p = 0.008). The lasting effects of VR-based reminiscent intervention was evaluated after another 3 months interval. No significant changes in MMSE and CDR-SB were noted compared to the second evaluation except the significant decline in CASI score (p = 0.030). The innovative study has indicated the 3 months VR-based reminiscent intervention can prevent significant cognitive decline of AD, and the effects could last, at least, for another 3 months without receiving continuous intervention.
4.3 Weakness of current studies due to their heterogeneous study designs
These studies have some methodological limitations due to a small sample size and various study designs and measurements, which makes these studies inappropriate to generalize conclusions. Similarly, there were inconsistencies in the purpose of administrating VR-based intervention among patients at different stages of dementia and MCI. Moreover, VR is using a hardware to deliver the content, software which was designed by researchers and was usually the critical parts to interact or manipulate the participants to train their cognition, especially for various cultural background. The content of VR did not control and was hardly to be controlled in various study designs because of personalized characteristics for each user and patient, which usually has geographical difference and cultural features.
Besides, how to deliver the software with different interactive experiences has been described and discussed. In a broad spectrum, virtual reality, ranging from interactive computer-based programs using a joystick, mouse, or keyboard [52] to an immersive environment [53], and these various paths to deliver the software were also considerable heterogeneity in study design and make results difficult to be interpreted and compared. All of these inevitable different factors make these studies inclusive results and not easily to make meta-analyses reports. However, overall, the studies reported VR-based reminiscent intervention has high levels of interaction and immersion, revealing a considerable enjoyable and engaging experiences for elderly, MCI, and demented people with potential benefits.
4.4 Stages of dementia receiving the intervention of VR
Different stage and types of dementia have various pathophysiological changes in their brain and also harbor varied interactive potentials to external stimulus, VR-based reminiscent intervention. Testing evaluating the effects of VR-based reminiscent intervention should be targeted to investigate the different effects of such intervention to different stages and types of dementia. The use of VR-based reminiscent intervention for severe dementia has yet to be tested and may not be easy to be conducted and completed. Currently, most VR-based reminiscent intervention studies have focused on individuals with MCI or early-stage AD, suggesting that the newly developed technology could be more useful for these individuals, potentially slowing cognitive decline for they were well communicated to follow the instructions to using VR-based reminiscent intervention. However, another point should be made that VR-based reminiscent intervention could be tailored accordingly to provide comparably greater assistances in advanced stage patients for their higher prevalence of BPSD. The consistent study results have indicated that VR-based reminiscent intervention will decrease BPSD of patients and caregiver’s burden. In other words, a coming VR-based reminiscent intervention design should be made for the advanced dementia and their caregivers, particularly if use of the technology is relatively simple and safety screening is done prior to use.
5 Prospects when administrating VR
How to minimize the possible side effects when administrating VR is becoming an important issue although overall a small number of not severe side effects have reported in the VR studies, including confusion, difficulty, motion-related sickness such as vertigo, dizziness, nausea, or vomiting, and headaches [54]. If the VR user has the neck pain and vestibular dysfunction would be more cautious for the possible side effects [54]. For the risk of inducing hallucinations and balance problems after using VR intervention, patients having Lewy body dementia should be more cautious for themselves potentially having higher possibility of presenting hallucination throughout their disease courses [55].
Other health concerns for VR intervention including uncomfortable sensation of eye for long-term use and mood change secondary to the VR content with novel immersive experiences could be overcome and adjusted to make user safe and comfortable. Another potential limitation of VR intervention is the currently higher price of the wearing device to limit its extensive application. However, along with the improvement of manufacturing technology, the lighter and less expensive device with acceptable cost will extend the benefits of using VR.
In summary, along with more widespread application of the new technology, VR equipment may be individualized and be more delicately and precisely to deliver the well-designed interactively training program with better personal hygiene to increase the accessibility of VR intervention. More important, these interventions by VR highlight the new considerations in increasing diagnostic accuracy, providing possible treatment, digital therapy, and lowering the caregiver’s burden, which we have to face, to meet, and to work with various professionals.
Footnotes
Conflict of interests
All contributing authors report no conflict of interests in this work.”
Funding
There is no funding support for this article.
Authors’ contribution
YH Yang: the manuscript writing and data searching; RFV Situmeang and PA Ong: joined the discussion and provided feedback for the manuscript; RM Liscic joined the discussion and edited the manuscript.