A Scoping Review Of Cognitive Training in Neurodegenerative Diseases Via Computerized And Virtual Reality Tools: What We Know So Far Part 1

Abstract: 

Most prevalent neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and multiple sclerosis are heterogeneous in their clinical profiles and underlying pathophysiology, although they typically share the presence of cognitive impairment that worsens significantly during the disease. 

Neurodegenerative diseases are a class of diseases that affect the normal function of the central nervous system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, etc. The common feature of these diseases is the chronic progressive damage to neurons, which leads to the gradual degeneration of the patient's physical and cognitive functions. Among them, Alzheimer's disease is more common. The main manifestation of this disease is memory loss, also known as senile dementia.

As human life expectancy increases, the incidence of neurodegenerative diseases gradually increases, which also makes people pay more attention to the relationship between memory and neurodegenerative diseases. In medical research, it is found that many factors affect memory, such as environment, lifestyle, genetics, etc. One of the most important factors is cultural education. This is why people with higher education are less likely to suffer from neurodegenerative diseases than those with low cultural education. Because people with high cultural education will have more thinking and stimulation in daily life, this will also promote the connection and information transmission between brain nerve cells, improve memory, and make the brain function last longer.

In addition, proper exercise can also improve memory, not only physical exercise, but also brain exercise. Various ways can be used to stimulate the brain, such as reading, learning, games, etc. These activities can not only stimulate the brain but also enhance people's self-confidence and mood so that people can face life with enthusiasm.

In short, although neurodegenerative diseases have a great impact on people's cognitive functions, we can completely prevent and improve the impact of this disease on us through an active lifestyle and learning. Let us pay attention to cultural education, exercise, stimulate the brain, maintain an open-minded and optimistic attitude, face life positively, and keep our hearts young. It can be seen that we need to improve our memory. Cistanche can significantly improve memory because Cistanche is a traditional Chinese medicine with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from the various active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in many ways.

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Viable pharmacological options for cognitive symptoms in these clinical conditions are currently lacking. In recent years, several studies have started to apply Computerized Cognitive Training (CCT) and Virtual Reality (VR) tools to try and contrast patients' cognitive decay over time. 

However, no in-depth literature review of the contribution of these promising therapeutic options across main neurodegenerative diseases has been conducted yet. 

The present paper reports the state-of-the-art CCT and VR studies targeting cognitive impairment in most common neurodegenerative conditions. 

Our twofold aim is to point out the scientific evidence available so far and to support health professionals to consider these promising therapeutic tools when planning rehabilitative interventions, especially when access to regular and frequent hospital consultations is not easy to provide.

Keywords: Alzheimer's disease; cognitive impairment; frontotemporal dementia; multiple sclerosis; neuropsychology; Parkinson's disease.

1. Introduction

Neurodegenerative diseases such as Alzheimer's disease (AD), Frontotemporal Dementia (FTD), Parkinson's disease (PD), and Multiple Sclerosis (MS) are a public health priority throughout the world with tremendous medical, psychological, and economic repercussions. 

Their prevalence and incidence have dramatically increased with age over the last decades, and they are expected to continue to grow due to the gradual rise in the average length of life in most countries [1]. 

Neurodegenerative diseases are heterogeneous in their clinical profiles and underlying pathophysiology, although they typically share the presence of significant cognitive impairment. Time and accuracy of diagnosis are crucial factors, as they would allow the planning of timely and appropriate management of cognitive deficits. 

As no effective pharmacological treatments for cognitive symptoms in this clinical domain are currently available, in recent years, various studies have started to investigate the potential contribution of Computerized Cognitive Training (CCT) and Virtual Reality (VR) tools in contrasting patients' cognitive decay (see for example the systematic review by Hill and colleagues [2], with a specific focus on mild cognitive impairment and dementia). 

Even if the use of these remote tools was considered a promising therapeutic option from the very beginning, the severe COVID-19 pandemic has made it evident the essential need to plan remote interventions implemented by patients and caregivers without the need for them to go repeatedly to hospitals and clinics. 

After presenting the most prominent neuropsychological features of the major neurodegenerative diseases here considered, the present in-depth review reports the state-of-the-art CCT and VR studies targeting cognitive impairment in these clinical conditions. 

Our twofold aim is to consider what has been done so far in the field and to highlight how these therapeutic options can help health professionals manage more effectively the cognitive deficits that characterize patients' profiles while reducing significantly the number of visits to clinics.

1.1. Neuropsychological Profiles of Main Neurodegenerative Diseases

Alzheimer's disease (AD) is a highly disabling neurodegenerative disorder that represents more than 60% of dementia diagnoses among the elderly worldwide. 

Neurophysiology of AD is mainly characterized by the extra-cellular accumulation of amyloid-β peptide plaques and intracellular neurofibrillary tangles containing phosphorylated tau protein on cortical and sub-cortical regions [3]. 

These physiological abnormalities undermine cerebral integrity, causing global white and grey matter atrophy involving frontal regions, cingulate and temporal cortex and praecuneus, selective hippocampal atrophy, and increased ventricular volume [4,5]. 

However, the connection between increasing amyloid plaques and the manifestations of main cognitive deficits that typically characterize patients' profiles seems to be not so direct, as treatments aimed to reduce amyloid accumulation are relatively useless in contrasting cognitive decline [6,7]. 

The first neurophysiological abnormalities affect medial temporal lobe structures involved in memory [8], semantic retrieval [9], and spatial processing [10]. As a result, early cognitive changes typically involve progressive memory loss, reduced visuospatial attention, and topographical disorientation [11–13], especially in early-onset AD [14]. 

Then, the disease progression spreads on a large scale [15], causing anterograde amnesia [16] and significant impairment in the realm of executive functions [17]. During the early stages of the condition, it is not trivial to differentiate AD from pre-clinical manifestations that require attention such as Mild Cognitive Impairment (MCI) [18,19]. 

AD cognitive deficits and comorbidity with neuropsychiatric disorders such as depression, anxiety, aggressiveness, and disinhibition heavily affect the Quality of Life (QoL) of both patients and caregivers [20,21]. 

Preservation of autonomy in performing an instrumental activity of daily living and intervention to improve cognitive functions seem to directly affect improving QoL scores [20,22]. 

A definitive cure for AD has not been found yet, since etiology is still unknown and pathogenesis unclear [23]. For this reason, main therapeutic protocols can only try to attenuate disease progression by reducing symptoms or delaying their onset to maintain a sufficient level of physical, psychological, and social functioning [24]. 

Usually, such interventions are designed to improve individual goal-directed behavior and require the active participation of caregivers and professionals [25]. Frontotemporal dementia (FTD) is a neurodegenerative disorder that shares various clinical aspects with AD. 

Differential diagnosis is not trivial in the earliest stages of the disease's progression, and cognitive screening tools such as the Mini-Mental State Examination (MMSE) are not sensitive enough to differentiate between FTD and AD [26]. 

The main differences in the behavioral domain regard the loss of social and personal awareness and the presence of stereotyped repetitive behaviors in FTD [27,28], while on the cognitive side, it lacks significant memory deterioration. 

Episodic and autobiographical memories are relatively well preserved since no hippocampal deterioration has been observed in FTD, especially in the early stages [29,30]. 

Importantly, FTD develops earlier and progresses faster than AD [31,32], making an efficient diagnostic process even more crucial for this condition. Clinical manifestations of FTD are heterogeneous and include a first distinction between a behavioral variant (bvFTD) and primary progressive aphasia (PPA), with the latter further divided into semantic (svPPA), non-fluent (nfvPPA) and logopenic (lvPPA) variants. 

The behavioral variant (bvFTD) is characterized by the deterioration of frontal and prefrontal cortices which determine behavioral abnormalities and impairments of executive functions, working memory, and social cognition [33–35]. Regarding PPA, its semantic variant (svPPA) is characterized by degeneration of the left anterior, middle, and inferior temporal cortices [36,37]. 

The main cognitive symptoms of svPPA include loss of semantic memory in both verbal and non-verbal domains, impaired word comprehension, and difficulties in recognizing the names and faces of known people. 

Impairments in performing non-verbal tasks suggest the gradual disruption of the conceptual knowledge system rather than a purely language-related condition [38]. The non-fluent/agrammatic variant (nfvPPA) is characterized by cortical atrophy in the left inferior frontal gyrus, premotor cortex, and anterior insula [39] and its main cognitive deficits are evident in agrammatic speech, in the comprehension of syntactically complex sentences, and the apraxia of speech, while single-word understanding and semantic knowledge are usually preserved [30,40]. 

The logopedic PPA (lvPPA) is characterized by atrophy of the left posterior temporal cortex and inferior parietal lobe, resulting in anomia, dysfluency, impaired repetition of sentences, and impairment phonological and syntactic level of lexical processing [30] (Gorno-Tempini et al., 2011). Parkinson's disease (PD) is characterized mainly by motor impairment including tremors, akinesia, rigidity, and postural instability. 

It is now well established that cognitive decline as well as difficult emotional processing is a major disabling PD symptom [41–43]. In many cases, impairment in the cognitive domain could be typically classified as full-blown MCI [44]. 

Neuropsychological assessment of the cognitive domain in PD patients usually highlights mild to moderate deficits in the visuospatial domain, attention, and working memory (WM), and a general decrease in executive functions [45] leads to significant behavioral symptoms too. 

Because these changes have a significant impact on the healthcare costs and quality of life (QoL) of both patients and their caregivers [46], it is a priority to identify effective intervention strategies to slow down cognitive deterioration. 

To this purpose, pharmacological treatments have failed at addressing and ameliorating cognitive symptoms in patients with PD [47,48], while a series of non-pharmacological approaches, consisting of cognitive stimulation and/or non-invasive brain stimulation [49], had attracted increasing interest over the last few years. 

Similar to PD, patients affected by Multiple Sclerosis (MS) are often affected by cognitive dysfunction [50–52], in addition to prominent motor and neuropsychiatric deficits [53]. 

In particular, cognitive impairment is observed in processing speed and attention, executive functions, memory, and even some aspects of language [54]. Such changes hurt the QoL of patients.

1.2. Neuropsychological Profiles of Main Neurodegenerative Diseases

To delay the onset of cognitive symptoms and slow down cognitive decline, Computerized Cognitive Trainings and Virtual Reality were revealed to be useful tools [2,55]. Computerized Cognitive Training (CCT) is usually based on protocols in which tasks aimed to improve and train cognitive functions are performed using electronic devices such as computers, tablets, and/or smartphones [56–59]. 

Virtual Reality (VR) and Augmented Reality (AR) are particular kinds of CCT. In VR, subjects interact with computer-generated environments which are built by researchers to control environmental variables and simulate multimodal experiences [60]. 

VR protocols can be differentiated by the kind of activity performed and technology adopted to provide a more or less immersive environment [61]. Non-immersive Virtual Reality (VR) consists of computerized protocols simulating real environments on 2D screens. 

In contrast, the term fully immersive Virtual Reality (VR), refers to a computer simulation that replaces the external sensorial world of the subjects with a three-dimensional artificial environment in which subjects can move or interact as if it were a real environment [62]. This immersion can be achieved using Head Mounted Displays (HMD) or particular rooms with the artificial environment projected on the walls and motion capture devices as in the Cave Automatic Virtual Environment (CAVE) system [63]. 

Currently, interactions with virtual environments in VR are mediated by the adoption of devices that collect motor responses (i.e., buttons) or sensors that collect motion of body parts (i.e., motion-captures camera, accelerometers, and eye-tracking), but the future implementation of brain-computer interfaces as controlling devices could potentially lead to higher levels of immersion in VR [64]. 

In AR, additional computerized objects are simulated overlaid to the real-world environment viewed through HMD, special goggles, or other devices like smartphones to stimulate interaction with simulated objects or integrate simulated features on real objects without the need to build a completely simulated virtual environment [65,66].

2. Materials and Methods

To ensure the reproducibility of our research, based on the guidelines for scoping reviews proposed by Arksey and O'Malley [67], we:

1. Identified our research question as "What is known so far from the existing literature about CCT and VR studies targeting cognitive impairment in most common neurodegenerative conditions?" In particular, we aimed to point out the scientific evidence currently available to provide support for health professionals to consider these promising therapeutic tools when planning rehabilitative interventions. 

2. Identified relevant studies which would be as comprehensive as possible in answering our central research question. To this purpose, we adopted a strategy that involved searching for research evidence via different sources (electronic databases, reference lists, hand-searching of key journals). In the first step, we performed an EBSCO, Google Scholar, and PubMed-based search using these specific combinations of keywords: "Cognitive Training" OR "Virtual Reality Training" "Augmented Reality Training" OR "telerehabilitation" AND "Alzheimer's disease" OR "frontotemporal dementia" OR "Parkinson's disease" OR "Multiple Sclerosis". 

Since we were interested in exploring the latest evidence, we focused our literature search on articles that have been published between 2015 and 2020. However, we also included previously published articles whenever necessary to clarify the information that emerged from more recent studies. Successively, the review was further extended by considering all relevant articles reported in the references of each paper 

3. Selected the studies adopting inclusion and exclusion criteria, based on our specific research question. Analysis has been primarily focused on studies reporting details about cognitive training, patients' characteristics, presence/absence of cognitive symptoms, study design, experimental protocols, quantification of training parameters of interest (in terms of length and frequency of training sessions), and brain imaging data, where available. We excluded research on healthy subjects and/or conducted in non-human animals. Finally, Duplicates and/or redundant resources across databases were removed. Figure 1 reports the following flowchart. 

4. Charted our data, summarizing the relevant aspects of our selected studies. We recorded information as follows: Authors, Year published, Size of the sample, Diagnosis of the clinical sample, Mean age of the sample, Duration of the intervention/training, Study type, Type of experimental control condition or group, Cognitive training used, Main results, Duration and presence of a follow-up (see Tables 1 and 2). 

5. Summarized and reported our narrative account of findings, organizing the literature thematically according to a first criterion (type of neurodegenerative disorder) and an ensuring second criterion (kind of CCT and VR training/intervention).

3. Results

3.1. Alzheimer's Disease (AD)

3.1.1. Computerized Cognitive Training (CCT)

Cognitive training (CT) interventions are based on protocols specifically designed to reduce the degeneration of cognitive functions mainly impaired in AD, such as memory, attention, and problem-solving to restore individual global functionality [68]. 

Cognitive training interventions in AD are valuable. Their efficacy in delaying impairments and improving global cognitive functioning has been documented in some studies [69–71]. Other studies failed to show a positive effect. However, cognitive training could be problematic since poor performances could be associated with reduced therapeutic engagement, increasing frustration and depression [72]. 

During the last decade, easier access to electronic devices and the need for therapy from large populations had determined a wide widespread use of CCT as a technological aid, especially in cases of in-home therapy (or Telerehabilitation) for bedridden patients [73] or in case of pandemic events which had required social isolation [74]. 

CCT utilization for cognitive rehabilitation and treatment of psychiatric diseases is controversial [75–79]. First, there are worries about conflicts of interest from companies that advise their product to overestimate their efficacy for commercial purposes [80]. 

Moreover, other crucial issues in demonstrating CCT's efficacy are the large variety of methodologies and outcome measures across studies [81], and it is still unclear whether effects on cognition are prolonged over a long-time range or can boost cognition only for a short time after the end of training [82,83]. However, a recent meta-analysis of 12 randomized controlled trial studies showed that CCT could significantly improve cognitive functions, especially in the memory domain with less extent in the attention, language, and executive functions domain in patients with mild AD and MCI [84]. 

Different CCT protocols have been observed to be more effective on MCI and early-stage AD patients compared to other neurodegenerative conditions and healthy individuals [81,85]. 

Cognitive interventions targeting early-stage AD are particularly effective [68,86] since, at that stage, cognitive functions are impaired but still show residual functionality. Alescio-Lautier and colleagues [87] used computerized visual recognition memory tasks and visually focused attention tasks together with a pencil paper semantic task with mild-AD patients. 

Their CCT protocol's difficulty was set on each patient's individual needs to reduce distress and maximize positive feedback that affects therapeutic outcomes [72]. 

After 15 sessions of training (from 90 to 120 min every two weeks), they observed improvements in Mini-Mental State Examination (MMSE) scores, memory recall, and verbal fluency while the control group showed a decline in performances. 

Cavallo and colleagues [88] adopted a CCT protocol including tasks that targeted different cognitive functions impaired in early-stage AD (i.e., memory, attention, executive function, and language) and whose difficulty was tailored to each patient's performance. 

A total of 80 early-stage AD patients were recruited and divided into an active and control group. The structured CCT protocol was administered to the active group for 30 min, 3 days a week, for 12 weeks. 

The control group performed unstructured general computerized tasks (e.g., reading articles, listening to music, watching videos) for the same time and with the same frequency as the active group. 

After the training period, patients in the active group showed significant improvements in different neuropsychological measures involving different cognitive functions than the control group. This pattern was stable at the 6-month follow-up. Crucially, in some tasks related to executive functions and memory, patients' performance in the active group increased after training. 

In contrast, the performance of patients in the control group decreased over time. This pattern suggests that structured computerized cognitive intervention could delay cognitive decline and improve cognitive functions in early AD patients. 

Another open issue regards the duration of beneficial effects induced by CT. Most of the interventions did not last beyond six months so little is known about the effect of these programs on AD patients after six months of treatment. 

In a recent study by Rodríguez-Mora and colleagues [89], the authors evaluate, in a sample of thirty-nine AD patients, the efficacy of the twelve-month Comprehensive Program of Cognitive Training (CPCT) consisting in a set of cognitive stimulations, intervention in activities of daily life (ADL), and motor training lasting 12 months. 

All patients were evaluated at baseline and in three-month intervals via the MMSE, the Cambridge Cognitive Examination (CAMCOG), the Lawton Instrumental Activities of Daily Living Scale (IADL), and the Global Deterioration Scale (GDS). 

The authors found no signs of mental decline between the baseline and 12-month stages since there were no significant differences in the MMSE, IADL, and GDS evaluations. 

On this ground, the authors concluded that the CPCT extends the benefit of non-pharmacological interventions for AD patients to twelve months and that its implementation might provide the patients' relatives with some guarantee concerning the delay of the disease.

A crucial issue is to provide effective continuative therapies to stimulate patients' cognition. With caregivers' cooperation, it is possible to administrate useful, cheap, user-friendly CCT directly at home. 

The efficacy of daily CCT on the ability to use a tablet has been observed by Imbeault and colleagues [90]. They tailored intervention on an AD patient with severe episodic memory deficit in a single case study. The patient was trained to use the tablet to schedule fictional appointments and, finally, be tested by scheduling and participating in real ones. 

Moreover, the patient improved her ability to use other different applications on the tablet and reported reduced daily-life problems and improvement in memory abilities since the tablet was introduced. This study suggested the impact of portable tablet and smartphone applications on global functional improvements [91,92]. 

Neuropsychological improvements using another in-home CCT battery have been found by Lizio and colleagues [93]. Their protocol consisted of 7 different tasks involving different cognitive functions, including visuomotor functions, visuospatial and planning frontal executive functions, short-term visuospatial episodic memory, visuospatial attention, and a central executive functioning task administered in the form of serious games [94,95]. 

After 15 days of daily training, participants showed improvement in accuracy and reaction times in all tasks. Administration of CCT in the form of a memory-based iPad game has been associated with greater engagement from aMCI patients, showing robust episodic memory improvements, together with greater self-confidence, self-rating of memory ability, and motivation [96]. 

A recent systematic review on the efficacy of in-home telerehabilitation [97] showed that its effects on cognitive abilities are comparable to conventional face-to-face interventions, highlighting the need for further research with comparable methodologies and measurements to demonstrate the in-home treatment valid alternative to classical treatments.

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