Effects of computerized cognitive training on neuroimaging outcomes in older adults: a systematic review

Background Worldwide, the population is aging and the number of individuals diagnosed with dementia is rising rapidly. Currently, there are no effective pharmaceutical cures. Hence, identifying lifestyle approaches that may prevent, delay, or treat cognitive impairment and dementia in older adults is becoming increasingly important. Computerized Cognitive Training (CCT) is a promising strategy to combat cognitive decline. Yet, the underlying mechanisms of the effect of CCT on cognition remain poorly understood. Hence, the primary objective of this systematic review was to examine peer-reviewed literature ascertaining the effect of CCT on both structural and functional neuroimaging measures among older adults to gain insight into the underlying mechanisms by which CCT may benefit cognitive function. Methods In accordance with PRISMA guidelines, we used the following databases: MEDLINE, EMBASE, and CINAHL. Two independent reviewers abstracted data using pre-defined terms. These included: main study characteristics such as the type of training (i.e., single- versus multi-domain), participant demographics (age ≥ 50 years; no psychiatric conditions), and the inclusion of neuroimaging outcomes. The Physiotherapy Evidence Database (PEDro) scale was used to assess quality of all studies included in this systematic review. Results Nine studies were included in this systematic review, with four studies including multiple MRI sequences. Results of this systematic review are mixed: CCT was found to increase and decrease both brain structure and function in older adults. In addition, depending on region of interest, both increases and decreases in structure and function were associated with behavioural performance. Conclusions Of all studies included in this systematic review, results from the highest quality studies, which were two randomized controlled trials, demonstrated that multi-domain CCT could lead to increases in hippocampal functional connectivity. Further high quality studies that include an active control, a sample size calculation, and an appropriate training dosage, are needed to confirm these findings and their relation to cognition.


Background
With our ageing population, the incidence of dementia is rising rapidly. Currently, over 47 million people worldwide are diagnosed with dementia and this number is expected to triple by 2050 [1]. In 2010 it was estimated that the worldwide cost of dementia was 604 billion US dollars [1]. Thus it is imperative to find strategies that promote cognitive healthy aging to minimize the projected societal, health, and economic burden by reducing or delaying the potential progression to mild cognitive impairment or dementia.
Currently, there is no pharmaceutical cure for dementia. As such, identifying lifestyle approaches that may prevent, delay, or even treat cognitive impairment and dementia in older adults is becoming increasingly important [2]. Even when an effective pharmacological therapy is available, lifestyle approaches (i.e., exercise, nutrition, and cognitive training) can be used in conjunction as lifestyle interventions result in multidimensional benefits [3]. In recent years, there is growing interest in complex mental activity as a strategy to promote healthy cognitive aging. Complex mental activity comprises all activities that are cognitively challenging for an individual [4], such as memory and executive functioning training, or dance. A meta-analysis of human cohort studies provides robust evidence that complex patterns of mental activity in early, mid-life, and late-life stages is associated with a significant reduction in dementia incidence [5]. Furthermore, they found an association between increased levels of complex mental activity in late life and lower dementia rates, independent of other predictors. Finally, it showed a dose-response relationship between the amount of complex mental activities in late life and dementia risk [5].
Computerized cognitive training (CCT) is one example of complex mental activity that could be used to promote healthy cognitive aging. CCT is defined as cognitive training on an individual electronic device (e.g., computer, laptop, tablet/iPad) that requires a physical response such as a button press, and excludes training that primarily requires an individual to perform two tasks simultaneously, in order to compare performance with single-task conditions (i.e., dual-task training). Notably, CCT is an approach that could be used by those who are limited in their ability to physically participate in other strategies, such as exercise. A meta-analyses shows that CCT improved overall cognitive performance in older adults [6]. Specifically it showed improvements in verbal and non-verbal memory, working memory, processing speed, and visuospatial skills [6]. Recent randomized controlled trials (RCT's) of CCT in older adults showed that both two and three months of training resulted in improved global cognition compared with an active control group [7,8]. Additionally, an RCT showed that CCT resulted in improvements in memory and processing speed which were still visible twelve months post-training [7], and shows that CCT is able to maintain its benefits. Playing a real-time strategy video game for 23.5 h improved performance in executive functions, indicating transfer of training after participating in complex mental activities [9]. Thus, current evidence suggests that CCT is a promising strategy for promoting healthy cognitive aging.
Cognitive training is based on the notion that the brain, even with age, can change for the better, if given the appropriate environmental stimuli, thoughts, and emotions [10]. This capacity of the brain is called "neuroplasticity". In the same way that physical training improves physical abilities, cognitive training (or brain training) may induce neuroplastic changes in the brain, resulting in improved cognitive abilities. One of the fundamental principles of neuroplasticity is the concept of synaptic plasticitythe notion that individual connections within the brain are constantly being removed or recreated, largely dependent upon how they are used [11]. Cognitive training aims to harness this principle of neuroplasticity by using guided practice on a set of tasks related to memory, attention, or other cognitive processes.
To gain more insight in what potential neuroplastic changes CCT may induce; incorporating different neuroimaging techniques in studies could be a good approach to help demonstrate these changes in the brain. For example, synaptic plasticity as a result of stimulation by CCT could potentially be captured by functional connectivity, measured with resting-state functional magnetic resonance imaging (rsfMRI), by strengthening connections within and between networks [12]. To date, it is not well established how CCT impacts regional brain volume, functional activity, and functional or structural connectivity in older adults. Although work has been done among younger adults illustrating changes in functional activity in the middle frontal gyrus and superior and inferior parietal cortices after working memory training [13], these findings don't necessarily translate to an older adult population. Therefore, gaps remain in understanding the underlying mechanisms of training-induced neuroplasticity in older adults. Addressing this knowledge void, this systematic review aims to ascertain the mechanisms by which CCT exerts an impact on brain structure and function by using different neuroimaging techniques such as volumetric magnetic resonance imaging (MRI), task-based functional MRI (fMRI), rsfMRI, and diffusion tensor imaging (DTI). Through understanding the underlying neural mechanisms of CCT, our goal is to provide knowledge on how to design improved and targeted interventions that help combat or prevent cognitive decline throughout life.

Search strategy
In accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement [14], we conducted a comprehensive search of MEDLINE, EMBASE, and CINAHL databases to identify all the studies that investigated neuroimaging outcomes resulting from CCT interventions. We limited our search to adults aged 55 years and older with and without cognitive impairment, who have not been diagnosed with dementia. We did not limit the search based on publication date, as CCT is a relative novel research topic. The final search (see Fig. 1a for search strategy) was done on July 7 (2016) and included a check for recent publications in PubMed.

Study selection
We selected studies that had a CCT intervention with neuroimaging outcomes (e.g. volumetric structural MRI, functional MRI, DTI) in an older adult population (age 55 years and older). Study designs included in this systematic review were RCT's and quasi-experimental studies. Studies that used samples of younger and older adults but reported group results separately were included in this systematic review. We included studies that focused on both single-and multi-domain CCT programs. We considered single-domain CCT training as training that targeted a specific cognitive ability, such as working memory. In contrast, multi-domain CCT was considered training that consisted of a series of tasks that targeted multiple cognitive abilities (e.g., executive functions and memory). We excluded studies that did not focus on CCT or studies that used CCT in combination with other types of intervention (e.g., non-CCT, exercise), reviews and short reports. A full list of exclusion criteria and the exclusion pathway is displayed in Fig. 1b. Critical review of titles and abstracts resulted in 26 articles for full-text review.

Data extraction and quality assessment
We developed a list of data extraction items.  [15] was used to assess the quality of the included studies. We [LTB and TLA] added three additional items to the PEDro scale to ensure a proper assessment of intervention studies using neuroimaging outcomes. These three items included were: 1) cognition measured to assist the interpretation of neuroimaging results; 2) sample size calculation; and 3) compliance reported (yes/no). To answer the items in the quality assessment, we used a '+' for items that were present and a '-' for items that were absent. The quality assessment was performed independently by two authors [LTB and CKB]. Discrepancies were discussed and reviewed by two authors [JCD and TLA]. Consensus between two authors [LTB and CKB] was achieved after discussion (K=0.98). Because item one of the PEDro scale is related to external validity, it is not included in the overall PEDro score. Therefore, the maximum quality assessment score calculated by the PEDro was 10 points (each '+' indicates one point), and will be reported in the results. Studies with a PEDro score of 6/ 10 or higher were considered studies of moderate to high quality. The additional item list had a maximum score of three points and trends from this list will be descriptively discussed in the results.

Structural imaging (n = 4)
Four studies [16,19,20,22] reported volumetric and cortical thickness outcomes (Table 3). A randomized controlled study (full factorial design) multi-domain cognitive training study using Cogpack [19], older adults with mild cognitive impairment (MCI) trained for a total of 78 h over a period of 6 months under supervision. Combined cognitive training with resistance training resulted in increased cortical thickness in the posterior cingulate cortex. However, in the same study they found that cognitive training alone led to a decrease in the posterior cingulate cortex thickness. However, there was no difference in decrease in thickness compared with the control group.
In addition, a twelve-week supervised multi-domain CCT study [16] using the same program (CogPack) showed that 36 h of training resulted in an increase in grey matter density in the right post-central gyrus compared with a decrease in the active control group. Additionally, the training resulted in a difference in rate of thickness change over time in both the left fusiform gyrus and the supramarginal and post-central gyri.
In contrast, in an object-location learning paradigm study [20] participants performed training on three consecutive days where they had to learn the correct spatial location of buildings on a street map. On each training day, the training was followed by a cued recall and recognition task. Hippocampal volumes was measured pre-and post-training. The authors found that the object-location learning paradigm did not lead to changes in hippocampal volume.
In another quasi-experimental study [22], participants performed an adaptive working memory training (n-Back) for twelve 45-min sessions over 4 weeks. Difficulty level of the training was based on individual performance and increases over time. Results showed that the training did not result in changes in grey matter volume in the working memory network.
In summary, one RCT [19] found cortical thinning as a result of cognitive training alone. In contrast, another RCT [16] found an increase in grey matter density following training. Finally, one study [22] found that cognitive training did not result in changes in grey matter, and one study [20] found that cognitive training did not lead to changes in hippocampal volume.

Task-based fMRI (n = 3)
Three [18,21,22] of the eight included studies examined the effect of a CCT intervention on brain function as    Belleville et al.    This dual-task cost represents the proportional loss of performance in the dual-task condition as a function of performance in the single-task condition. A larger score represents a larger dual-task cost c Not specified whether correlations were based on change scores or scores at week 10 d Results reported for all older participants (N = 19) measured via task-based fMRI (Table 3). An RCT [18] showed that 2200 min of cognitive training over a period of 5 weeks resulted in a significant increase in left anterior hippocampus activity compared with an active control group. The cognitive training consisted of seven games aimed to improve auditory processing speed and accuracy. Task difficulty was adjusted throughout the training based on individual performance. The active control group performed computer-based activities such as reading online newspapers and playing computer games targeting visuospatial abilities. A two-week quasi-experimental study looked at focused and divided (fixed and variable) attention training [21]. In the focused attention training, two tasks (i.e., alphanumeric task and a visual detection task) were performed back to back but separate so participants focused on one task at a time. In the divided attention training, participants performed two tasks at the same time with an equal amount of attention (fixed) or under different attention allocations (variable). Results showed that training a single alphanumeric task for 6 h over two weeks decreased activation in the inferior and right middle frontal gyrus, in the left middle frontal gyrus and in the left thalamus. No differences in functional brain activation were found after performing the single visual detection task or the in the dual task condition. Participants who were assigned to training where they performed both the alphanumeric task and the visual detection task at the same time (i.e., dual task) did not show differences in performance during the alphanumeric task in the scanner. However, participants showed decreased functional brain activation at posttraining compared with pre-training in the cerebellum and right middle occipital gyrus during the single visual detection task. Additionally, participants showed a slight increase in activation in both the right and left middle frontal gyrus. Finally, participants who were assigned to the training group where they had to perform dual tasks under different attention allocation levels (i.e., 80%, 50%, or 20%), showed increased activation in the right middle frontal gyrus (area 10) for 20% and 50% attention allocation when performing the dual task. No significant changes in functional brain activation were found during the 80% attention allocation task, neither during the alphanumeric single task, nor during the visual detection single task performance.
In an adaptive n-back training program [22], participants performed 12 sessions of approximately 45 min each over 4 weeks. The difficulty level of the training was based on individual performance and was increased across training sessions by increasing working memory load and decreasing the interstimulus interval. Results of this study showed a non-significant time (2) by working memory load (3) interaction, with a significant main effect of time. This main effect of time demonstrates a reduction in working memory network functional brain activity measured by the Blood Oxygen Level Dependent (BOLD) signal after 12 training sessions. Only decreases in the 1-back (and not 2-back or 3-back) condition were significant, which indicates this main effect of time is driven by the BOLD signal during the 1-back condition.
In summary, an RCT [18] showed that 2200 min of CCT resulted in increased in left anterior hippocampus activity compared with an active control group. One quasi-experimental study [21] showed that depending on the task and region of interest, all training conditions resulted in both increased and decreased activity. Finally, a second quasi-experimental study [22] found that 12 sessions of n-back training resulted in a significant decrease in working memory activity; however decrease in activity was driven by performance on the 1-back condition.

Resting-state fMRI (n = 5)
Five studies [16,17,19,22,24] looked at changes in functional connectivity after CCT (Table 3). An RCT [19] examined the effect of progressive resistance training (PRT), computerized multi-domain cognitive training (CCT), or a combined intervention on brain structure and function in older adults with mild cognitive impairment (MCI). The study duration was 26 weeks, with a total of 78 h of training. In the cognitive training groups (i.e., PRT + CCT, and CCT + Sham), the posterior cingulate cortex showed significant decreases in resting-state functional connectivity with both the superior frontal lobe and the anterior cingulate cortex. In addition, increases in resting-state functional connectivity between the hippocampus and the left superior frontal lobe were found compared with groups without CCT.
A second RCT of 12 weeks of multimodal CCT [16] showed that 36 h of cognitive training resulted in decreases in resting-state functional connectivity between the posterior cingulate and the right superior frontal gyrus, while the control group showed significant increases in resting-state functional connectivity. In contrast, CCT resulted in increased resting-state functional connectivity between the right hippocampus and the left superior temporal gyrus compared with a decrease in connectivity in the control group.
Another RCT [17] looked at the effects of a 10-week computer assisted training focused on executive functioning and memory in older adults with a history of stroke. The authors found that training, compared with a passive control group, significantly increased restingstate functional connectivity in multiple areas. The left hippocampus showed significantly increased connectivity with the right inferior frontal gyrus and the right middle frontal gyrus. Additionally, the right hippocampus showed increased resting-state functional connectivity with the left middle frontal gyrus, the left inferior frontal gyrus, the left superior frontal gyrus and the left parietal lobe. In contrast, the control group showed significant decreases in resting-state functional connectivity over the 10 weeks (see Table 3 for connectivity decreases).
A quasi experiment investigating the effect of three different computer programs [24] found an increased resting-state functional connectivity in the dorsal network between the right superior parietal cortex (SPC) and left posterior inferior temporal lobe (ITL) in Rise Of Nation (RON) compared with a decrease in Space Fortress (SF). Finally, Brain Fitness (BF) resulted in significantly decreased resting-state functional connectivity between the right SPC and the left anterior ITL compared with an increase in RON.
Finally, a quasi-experimental study [22] looking at the effects of an adaptive n-back training program in older adults found that the 5-week training did not result in changes in task-based functional connectivity in the working memory network.

Structural connectivity (n = 4)
Four studies [16,20,23,24] examined changes in structural connectivity, using DTI, after CCT (Table 3). Whole brain diffusion tensor imaging (DTI) of an RCT of 12 weeks of multimodal CCT [16] showed that 36 h of cognitive training did not result in changes in structural connectivity after training.
A quasi-experiment in healthy older adults looked at the effect of three different training protocols on brain structure [24]. The participants trained for 36 h over a period of 6 weeks; half of the training was supervised, and the other half was performed at their own homes. One training group performed BF, an auditory perception game; the second training group performed SF, a complex skill acquisition game focused on visuomotor and working memory skills; and the third group performed RON, an off-the shelf real-time strategy game focused on for example attention, motor processing, working memory and reasoning. The authors found changes in the ventral and dorsal network. Axial diffusivity (AD) was increased in the right occipito-temporal white matter in the BF group, compared with a decrease in SF and RON.
Another quasi-experimental study [23] of approximately 100 h of multi-domain cognitive training in both young and healthy older adults performed Diffusion Tensor Imaging (DTI) to look at the effects of training on structural connectivity in the brain. Result showed a significant decrease in MD in the genu of the corpus callosum compared with a passive control group who showed no changes in MD. They also found a significant increase of fractional anisotropy (FA) in the genu of the corpus callosum compared with the control group.
Diffusion Tensor Imaging results from a third quasiexperimental study [20] that involved 3 consecutive days of training an object-location learning paradigm, showed that the 3-day training resulted in a significant decrease in mean diffusivity (MD) in the fornix at post-training compared with pre-training. No changes in MD were found in the hippocampus as a result of the training. In addition, the results showed an increase in FA in the fornix, however this increase was not significant.
In summary, the seven [16,17,19,20,[22][23][24] above mentioned rsfMRI and DTI studies showed both increases and decreases in functional and structural connectivity after CCT. The variety in study protocol (i.e., training type, duration) and the regions of interest chosen for neuroimaging analysis makes the comparison between studies difficult.

Correlation between imaging outcomes and cognitive function outcomes (n = 8)
Eight studies [16][17][18][19][20][21][22]24] assessed the association between cognitive performance and neuroimaging findings (Table 3). An RCT in older adults with a history of stroke [19] found that increases in posterior cingulate grey matter were associated with improvements in global cognition. Additionally, a cognitive training by time interaction showed that the increased connectivity between the hippocampus and the left superior frontal lobe was related to increased memory domain performance. However, this interaction takes into account all training groups that had a cognitive training component (i.e., also cognitive training combined with resistance training). The inclusion of the combination group might have influenced this interaction.
In contrast, an RCT looking at CCT in older adults with MCI [18] found no significant correlations between neuroimaging and cognitive results. However, the authors found a non-significant trend suggesting that, in both groups, increases in hippocampal activity might be related to improved memory scores on the RBANS.
An RCT of multimodal CCT [16] found that increased grey matter density in the right posterior central gyrus was associated with improved global cognition at 3 weeks and 3 months. This association was found in both the training and control group. In addition, it was found that a decrease in resting-state functional connectivity between the posterior cingulate and the superior frontal gyrus after 3 weeks of training was related to an increased change in global cognition after 3 months of training. Increased restingstate functional connectivity between the right hippocampus and the left superior temporal gyrus measures after three weeks of training was associated with increases in global cognition after 3 months of training.
A quasi-experimental study [21] found that in participants performing the alphanumeric task in the single task condition (i.e., focus on one task at the time), there was a significant positive correlation between both the right inferior and the middle frontal gyrus activation and reaction time. Thus shorter reaction time (i.e., better performance) was associated with a decrease in brain activation. In the divided variable condition (i.e., dual task with different attention allocation levels), there was a negative correlation between activation of the right superior and middle frontal gyrus and attentional cost post training. This correlation indicates that a better training performance (i.e., lower attentional cost during dual task performance) was associated with higher levels of brain activation.
An RCT in older adults with a history of stroke [17] revealed that in the multimodal cognitive training group, resting-state functional connectivity between the left hippocampus and both the right frontal lobe and right frontal lobe, was associated with improved performance in memory executive function respectively. Additionally, increases in resting-state functional connectivity between the right hippocampus and the left frontal lobe and the left parietal lobe were associated with increases of memory and executive functioning. No significant associations between functional connectivity and behavioural performance were found in the control group.
A quasi-experimental study looking at the effect of three different types of cognitive training on brain structure and function [24] found that in the BF training group an increase in thalamic AD was associated with an increase in working memory performance. By comparing BF and SF, the authors found that an increase in occipito-temporal AD was associated with a decrease in everyday problem solving time. Additionally, they found an association between the increase in both the occipito-temporal AD and occipito-temporal-parietal AD and accuracy of spatial working memory tasks, indicating that a greater AD was associated with a smaller increase in accuracy on the memory task. Finally, looking at the contrast between SF and RON, functional connectivity decreases between the superior parietal cortex (SPC) and the posterior inferior temporal lobe (ITL) were related to better performance on every day problem solving tasks (i.e., decrease in time for task completion).
In another quasi-experimental study [20], participants training for 3 consecutive days on an object-location learning paradigm. The authors found that the previous mentioned increase in fornix FA on the post-test compared with pre-test was significantly associated with better recall performance. Thus, a higher increase in fornix FA over the course of the training resulted in a better recall performance on the object-location learning paradigm task. Changes in fornix MD, hippocampal MD, and hippocampal volume were not associated with recall performance. Performance on the episodic memory control task was not associated with changes in fornix FA.
The last quasi-experimental study [22] looked at changes in short term memory (digit span) and found a non-significant trend between task-based functional activation at baseline and improvement in digit span, which indicates that an increased activation might lead to increased short term memory performance.

Discussion
Findings from two high-quality studies examining the effect of CCT on volumetric changes, suggest that multidomain CCT programs with a duration ranging from 12 to 26 weeks could result in an increase in grey matter density [16], but in contrast could also result in a decrease in cortical thickness in the posterior cingulate [19]. This indicates that in a relatively short time span, multi-domain CCT might be able to alter brain structure. However, the overall heterogeneity of the findings between studies (i.e., potential functional improvements versus declines), which could be in part due to the differences in region of interest, makes it difficult to draw definitive conclusions regarding the effect of CCT on brain structure.
Task-based functional brain activity decreased after training of a single task [21]; however, an increase in task-based brain activation was found in a more complex dual-task training [21] and a multi-domain CCT program [18]. This highlights that the CCT method (i.e., multi-domain versus single domain CCT) may play a critical role in task-based functional brain activity. Conversely, multi-domain CCT did not result in changes in structural connectivity [16], where an auditory perception-training program resulted in increased AD [24]. Resting-state functional connectivity was found to increase [16,19] or decrease [16,19,24] depending on training type (e.g., single-versus multi-domain) and region of interest. Below, we will discuss as to why we PEDro scoring system: receive a point (+) for each item that is met. When criteria were not met (−), no points were given The maximum number of points is 10, which means excellent quality based on PEDro's quality assessment Additional Quality Assessment Items: Maximum score of 3 PEDro Scale 1. Eligibility criteria were specified (this item is not used to calculate the PEDro score) 2. Subjects were randomly allocated to groups 3. Allocation was concealed 4. The groups were similar at baseline regarding the most important prognostic indicators 5. There was blinding of all subjects 6. There was blinding of all therapists who administered the therapy 7. There was blinding of all assessors who measured at least one key outcome 8. Measures of at least one key outcome were obtained from more than 85% of the subjects initially allocated to groups 9. All subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least one key outcome was analyzed by "intention to treat" 10. The results of between-group statistical comparisons are reported for at least one key outcome 11. The study provides both point measures and measures of variability for at least one key outcome Additional Items 12. Was cognition measured to assist the interpretation of neuroimaging results? 13. Was there a sample size calculation? 14. Was the compliance reported? might see a discrepancy between single-and multidomain CCT effects, and why this discrepancy might affect both structural and resting-state functional connectivity differently.

Task-based functional activity
Functional activation patterns in the brain change with aging as a result of neurophysiological changes. Compared with younger adults, functional activation patterns become less coordinated and localized in older adults, which result in loss of cognitive performance [25]. In the current review, three studies looked at functional activity in the brain while performing a task in the scanner. Activity levels in the brain while performing a task were both increased and decreased, depending on the type of training and region of interest. All three studies focused on different brain regions, which makes comparison difficult. However, results suggest that engaging in a more diverse or complex training (e.g., multi-domain CCT or dual-task training) might lead to an increased functional activation [18,21] compared with training of a single task [21,22]. In contrast, a short report focusing on transfer of training showed results that five weeks of training (i.e., letter memory and updating tasks) resulted in increases in taskrelated functional activity in the striatum compared with a passive control group [26]. Though, besides the focus on different brain regions, the vast differences in study design, such as the training duration, the presence or absence of a control group, and the small number of studies ask for prudence for making assumptions.

Structural connectivity and type of training
DTI is an imaging technique used to determine the white matter microstructure of the brain by looking at how water molecules diffuse within the brain (i.e., the direction and amount of diffusion) [27,28]. DTI is often quantified by measures such as FA and MD; which provide information about the direction of diffusivity and molecular diffusion rate, respectively. Decreases in FA and increases in MD might indicate lower levels of myelin or the presence of axonal injury, as water molecules are able to diffuse more freely (i.e., isotropic) [29,30]. However, rather than looking at one specific DTI scalar (e.g., FA, MD), scalars need to be combined with other neuroimaging measures (e.g., T2, PD, FLAIR) to give a more detailed and accurate picture of for example white matter abnormalities that might occur within the brain [30]. Studies have linked loss of white matter integrity, as measured with DTI, to be associated with age-related cognitive decline in otherwise healthy older adults [31].
In addition, a meta-analysis focusing on DTI in MCI and Alzheimer's Disease found increased MD in both MCI and Alzheimer's Disease, as well as decreased FA in Alzheimers' Disease compared with controls. More severe levels of Alzheimer's Disease (i.e., lower scores on the Mini-Mental State Examination) were associated with reductions in FA [32].
Few studies looked at the effect of CCT on structural connectivity using DTI. One study of moderate-to-high quality (PEDro score of 7/10) found no changes in structural connectivity after 12 weeks of multi-domain CCT, which could be due to the small sample size [16]. These findings are in contrast with a quasi-experimental study [22] that found that an average of 100 h of training over four months resulted in decreased MD and increased FA in the genu of the corpus callosum. These findings suggest that multi-domain CCT is able to alter white matter microstructure in the brain in older adults. This finding could be promising as disruptions in white matter organization are often paired with cognitive decline [33]. However, a limitation of this quasi-experimental study is the lack of an active control group. Thus, we need more high quality studies to replicate these findings and to examine how multi-domain CCT might be able to alter white matter microstructure.
Increases in AD in the right occipito-temporal white matter were found in a study examining the effect of an adaptive auditory perception computer game (i.e., singledomain). This increased AD was correlated with a lower score in everyday problem solving and spatial working memory accuracy [24]. However, due to the absence of an included control group, this study used contrasts between the three training groups to look at improvements between groups. Therefore, results will more likely provide information about the effect of the training groups in relation to each other (i.e., which intervention shows the best results), than give information whether the intervention actually works.

Functional connectivity and type of training
Resting-state fMRI is used to map networks in the brain, such as the well-established Default Mode Network (DMN) and the Central Executive Network (CEN). These networks are activated in both the presence [34] or the absence of a (cognitive) task [35,36]. In patients with MCI or Alzheimer's Disease, these functional networks in the brain are found to be disrupted [37,38]. In addition, we can measure functional networks in the brain while performing a task with task-based fMRI.
Two studies [16,19] showed that a multi-domain CCT intervention resulted in increased resting-state functional connectivity of the hippocampus. One high quality study (i.e., PEDro score of 9/10) found that a 26-week multidomain CCT program alone (versus combination of CCT with resistance training) resulted in increased resting-state functional connectivity between the hippocampus and the left superior frontal lobe [19]. Additionally, a study with the same CCT program (i.e., COGPACK) found that multi-domain CCT resulted in increased resting-state functional connectivity between the right hippocampus and the left superior temporal gyrus after only three weeks of training [16]. These improvements in resting-state functional connectivity were significantly correlated with improved memory performance [19] and changes in global cognition at follow-up [16], respectively.
In accordance, an RCT of multi-domain CCT in older adults with a history of a stroke [17] found that CCT increased resting-state functional connectivity between the hippocampus and both the inferior frontal gyrus and the middle frontal gyrus. These increases in resting-sate functional connectivity were associated with significant positive changes in memory quotient and processing speed (Trail Making Test-A). Literature shows that resting-state functional connectivity between the hippocampus and the superior frontal lobe is reduced in MCI [37,38]. Therefore, the current findings might indicate that multi-domain CCT could lead to improved cognitive performance through strengthening hippocampal functional networks and preventing memory loss that might be manifested by loss in hippocampal functional connectivity. However, the biological underpinnings of this change in connectivity are still unclear. Current histological findings suggest training induced neuroplasticity could be a result of dendritic branching, synaptogenesis or other factors such as angiogenesis [39]. Besides more human studies, we need to combine knowledge acquired from both human and animal (histological analyses), to help understand how multi-domain CCT could result in these functional changes in the brain.
Immediate comparison between the results of a singleversus multi-domain program can be made within one quasi-experimental study [24]. Participants in this study were randomly assigned to one of three included cognitive training programs. Participants who were randomized in Brain Fitness, a training program considered more singledomain in nature, showed decreased resting-state functional connectivity between the superior parietal cortex and the inferior temporal lobe. In contrast, participants who were assigned to Rise of Nation, a more multi-domain training, showed increased resting-state functional connectivity between the superior parietal cortex and the inferior temporal lobe. This contrast could be due to the nature of the training (i.e., single-domain versus multi-domain), as another quasi-experimental study [22] of single-domain CCT showed no changes in task-based functional connectivity following training.
A recent study [40] comparing non-computerized single-domain and multi-domain training found that multi-domain cognitive training mainly resulted in increased memory proficiency, while single-domain training primarilybut not only -enhances visuospatial and attentional benefits. Results of the current systematic review are in accordance with these findings, as the multi-domain CCT shows improvements in restingstate functional connectivity of hippocampus-frontal lobe and hippocampus-temporal lobe, which was associated with improvements in memory. Single-domain CCT did not result in similar findings. Gains in cognition resulting from multi-domain were more prone to sustain compared to gains acquired in single-domain cognitive training. Thus, multi-domain cognitive training might result in more widespread gains in cognitive functions, which maintain visible over a longer period of time compared to single-domain cognitive training.

Quality assessment
The quality of studies was heterogeneous. Commonly missed criteria, were those that focused on blinding of participants, blinding of individuals who delivered the CCT, and blinding of the assessors. These issues could result into bias (i.e., either positively or negatively) during training and follow-up measurements due to expectations of both study examiners (treatment delivery or assessors) and participants. However, five [20][21][22][23][24] of the nine included studies were quasi-experimental and therefore the key characteristic of the more superior RCT, randomization into either an experimental or a control group, was lacking in these studies. The absence of a proper control group in these five quasi-experimental designs affects the interpretation of the results of the study; instead of whether a treatment works, quasi-experimental studies provide information on whether an intervention is more effective than a standard or alternative treatment.
Finally, of the three additionally included quality assessment criteria (i.e., item 12-14) two criteria (i.e., sample size calculation, compliance reported) were only met by one study [19]. The absence of sample size calculations and reported compliance in the remaining studies [16][17][18][20][21][22][23][24], could result in a lack of power, which increases the chances of false negatives (i.e., type-II errors). This could mean that potential effects of CCT on neuroimaging parameters simply could not be detected due to a small sample size, and not because they were not present.

Limitations
The studies included in this systematic review varied vastly in study design and CCT delivery, which resulted in a great deal of heterogeneity mainly in outcomes of functional and structural connectivity. Only four of the nine included studies were RCT's [16][17][18][19]. However, the type of control group used varied; some studies included active controls, whether other control groups were of a passive nature (i.e., usual care). The inclusion of a control group, with a preference for the so-called active control groups, is recommendable in future studies. In addition, the heterogeneity of the findings in this systematic review might also be due to the large variability in type of training (single-versus multi-domain) and the dosage and duration of training (i.e., days versus months). Thus, the heterogeneous nature of the study designs in this review makes it difficult to draw conclusions. To better understand the relevant mechanisms of CCT, neuroimaging outcomes need to be accompanied with behavioural data. Furthermore, there are limited investigations regarding the transfer effects of CCT and the pattern of neuroplasticity associated with transfer. A high-quality study design, which includes for example an active control group, a literature-based training duration and dosage, and a sample size calculation, would help increase the consistency and comparability of findings, which in turn would help increase the ability to draw appropriate conclusions.

Conclusions
This systematic review is an essential first step towards understanding the complex volumetric and functional changes, as well as changes in structural and functional connectivity that underlie CCT in older adults. However, the highly heterogeneous nature of the results in this systematic review, potentially due to the large variability in study design, indicates that more high-quality studies are needed to confirm and expand upon these findings. In addition, these studies do not provide information regarding the physiological and cellular mechanisms causing these structural changes. More histological studies are needed to gain insight whether these CCT induced changes might be a result of for example neurogenesis or synaptic plasticity. Future studies should focus on multi-domain CCT, since this type of training has the potential to induce more widespread and long-lasting effects on cognition. Availability of data and materials All data supporting the conclusions of this article are included within the article.
Authors' contributions LTB wrote the first draft of the manuscript. JCD and CKB provided helped with data extraction and drafting of tables. TLA and JCD conceived the study concept and design. TLA, JCD, and CKB wrote portions of the manuscript and critically reviewed the manuscript. All authors (TLA, JCD, CKB and LTB) have read and approved the manuscript.
Authors' information LTB is a Mitacs Accelerate Doctoral Trainee. CKB is a Michael Smith Foundation for Health Research Postdoctoral Fellow. TLA is a Canada Research Chair in Physical Activity, Mobility and Cognitive Neuroscience.
Ethics approval and consent to participate Not applicable.

Consent for publication
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