Exploring transfer effects on memory and its neural mechanisms through a computerized cognitive training in mild cognitive impairment: randomized controlled trial

Abstract

Background

Computerized cognitive training (CCT) has been proposed as a potential therapy for cognitive decline. One of the benefits of CCT is a transfer effect, but its mechanism on the memory domain is unclear. This study aimed to investigate the transfer effect of non‐memory multidomain CCT on the memory domain and its neural basis in patients with mild cognitive impairment (MCI) through a randomized controlled trial.

Methods

Patients with MCI recruited from memory clinics were randomly assigned to either the CCT or the control group. The CCT group received multidomain CCT training excluding memory training, while the control group read educational books with learning‐based quizzes twice a week for 8 weeks. Participants underwent memory tests yielding a composite score, other cognitive domain tests, non‐cognitive scales, and resting‐state functional magnetic resonance imaging (rsfMRI), at baseline and after intervention. Within‐ and between‐group comparisons, group × time interactions, and seed‐to‐voxel analyses in memory‐involving brain networks were performed.

Results

The CCT group showed improvement over the control group in memory domain (Group × time, F = 5.87, P = 0.03, η ² = 0.31), which was related with the increased connectivity in the hippocampal‐frontal and fusiform‐occipital network. No other cognitive and non‐cognitive symptoms differed between groups after adjusting for covariates.

Conclusion

Eight weeks of multidomain CCT without memory training improved memory function and restored functional network in the hippocampal and medial temporal region in MCI patients. These results can provide evidence for the transferring ability of CCT on memory functioning with its neural basis.

INTRODUCTION

Dementia poses a global health threat, impacting cognitive, psychological, and behavioural functions, as well as daily activities. Its socioeconomic burden surpasses that of any other disease. ¹ Although disease‐modifying immunotherapy offers new treatment avenues, ² preventing dementia and mitigating risk factors remain paramount. ³ Recent updates from the Lancet commission suggest that modifiable risk factors contribute to 40% of dementia cases globally, emphasizing the potential for prevention. ³

Considering modifiable risk factors, lifetime experience in mentally and cognitively engaging activities may protect against cognitive aging. ⁴ The concept of cognitive reserve relates with Alzheimer's disease (AD) pathology, clinical manifestations, ⁵ and structural and functional neuroimaging. ⁶ , ⁷ It also explains the model of neuroplasticity through cognitive intervention. ⁸ Recent technological advancements also have led to a development of computerized cognitive training (CCT) programs. ⁹ , ¹⁰ , ¹¹ Many cognitive training studies have shown minimal to moderate effect through traditional and computerized programs in old adults with normal cognition, mild cognitive impairment (MCI), and early dementia. ⁹ , ¹⁰ , ¹²

The transfer effect in cognitive training refers to the improvements not just in the same task but also in other explicitly untrained tasks. ¹³ Processing speed and reasoning training have shown a larger effect than sole memory‐targeted training, ¹⁴ with benefits to memory, ¹⁵ everyday functions, ¹⁶ and structural ¹⁷ and functional brain connectivity. ¹⁸ Varied training contexts in CCT may enhance transfer effects compared to fixed conditions, engaging users in coordinating cognitive domains, switching task paradigms, and stimulating cognitive reserve and neuroplasticity. ¹⁹ , ²⁰ Studies have found within‐domain or transfer effects of CCT on memory and executive functioning, including reasoning, processing, attention, and working memory. ²¹ However, the benefits to untrained domains of CCT are unclear, as the harmonizing nature of CCT may hinder differentiation between trained and untrained domains. Despite memory symptoms being common and early indicators of cognitive decline, the transfer effect of non‐memory CCT on memory domains has not been investigated.

The primary aim of this study was to test the hypothesis that multi‐domain CCT, excluding the memory domain, would have a transfer effect on the memory domain in MCI. We also explored the neural basis of the transfer effect on memory using resting‐state functional magnetic resonance imaging (rsfMRI). Secondary aims were to investigate the benefits of CCT on comprehensive cognition and non‐cognitive symptoms in patients with MCI.

MATERIALS AND METHODS

Participants

Patients with MCI were recruited from the memory clinic of the Gachon University Gil Medical Center and Inha University hospital, Republic of Korea, between December 2020 and December 2021. A total of 29 participants were randomly assigned to either the CCT or control group.

All participants met Petersen's criteria for MCI. ²² They had subjective cognitive complaints, including memory decline, but did not meet the criteria for diagnosis of a major neurocognitive disorder according to the Diagnostic and Statistical Manual of Mental Disorders‐5. ²³ Screening evaluation of the participants was performed by board‐certified psychiatrists.

Participants were excluded if they had any of the following: (i) a Korean version of Mini‐Mental State Examination (MMSE) score of <20; (ii) major psychiatric disorders including major depressive disorders; (iii) a history of any kind of dementia; (iv) impaired activities of daily living (ADL) (Barthel ADL Index of <20); (v) severe medical or surgical comorbidities; (vi) a history of neurodegenerative disorders; (vii) structural abnormalities on MRI; or (viii) an inability to use a tablet personal computer (PC) system.

All participants were informed about the study's aim, study protocol, group allocation, benefits, risks, and confidentiality, and provided written consent. The study was approved by the institutional review boards of both medical centres according to the Declaration of Helsinki (Gachon University Gil Medical Center: GCIRB2020‐451, Inha University Hospital: 2020‐10‐017‐001).

Study design

This study aimed to assess the transfer effect of CCT on memory symptoms in MCI in an open‐label, unblinded, randomized controlled trial. Participants were randomly assigned to the CCT or control group using a number list generated in Microsoft Excel. Before and after a 2‐month cognitive intervention, both groups were evaluated for memory, comprehensive cognitive function, non‐cognitive symptoms, and underwent rsfMRI. The CCT group received tablet PC cognitive training twice a week for 16 sessions, alongside usual therapy such as pharmacotherapy. Controls conducted educational book reading with learning‐based quizzes twice a week for 16 sessions.

Computerized cognitive training

The multidomain CCT program, developed between November 2018 and November 2020 by board‐certified psychiatrists and neuropsychologists, involved four cognitive domains: attention, language, visuospatial function, and frontal executive function. The CCT was developed based on previous studies regarding metamemory training programs developed by Youn et al. ²⁴ , ²⁵ Memory trainings, including verbal and visual memory, and even working memory trainings, were excluded in order to assess transfer effects on memory. Detailed contents and representative images for each category are presented in Table S1 and Figures S1 and S2 in the supplemental data.

Each session lasted 30 min, and the total duration of CCT was 8 h. Difficulty increased gradually every two levels (for a total of levels 1–8 across the 16 sessions). The CCT was conducted individually with automated informative feedback and assistance available. There were no revisions or breaches during the study period. An enhanced version of the CCT program is accessible online for free at https://play.google.com/store/apps/details?id=com.c2monster.LongLiveYouth&pcampaignid=web_share.

Educational book reading

The book reading material covered dementia and its prevention methods, with categories including normal aging, symptoms and causes of dementia, types of dementia, diet, physical activity, abstinence from alcohol and smoking, traumatic brain injury, and pharmacological treatment strategies. Participants memorized material and engaged in quiz sessions for reinforcement. Each session lasted approximately 30 min, with environmental conditions similar to the CCT group. Detailed contents and representative images are presented in Table S2 and Figures S3 and S4 in the supplemental data.

Assessments

Participants underwent comprehensive cognitive tests, psychiatric scales, and rsfMRI both at baseline and after the cognitive intervention period in a face‐to‐face manner. The baseline evaluations included several measures such as the Korean version of the MMSE, ²⁶ the Korean version of the Montreal Cognitive Assessment (MoCA), ²⁷ the Clinical Dementia Rating (CDR), ²⁸ the Korean version of the Barthel ADL (K‐ADL), ²⁹ the Korean version of instrumental activities of daily living (K‐IADL) scales, ²⁹ and the Korean version of the Mild Behavioural Impairment (MBI) checklist. ³⁰ Clinical and demographic information was collected, including smoking, alcohol consumption, history of depression, family history of dementia, and pharmacotherapy used for prevention of dementia such as choline alfoscerate and ginkgo biloba. The subjective state of vision and hearing impairment was assessed using a Likert scale ranging from 1 (mild) to 3 (severe).

Outcome measures

Primary outcome

The primary outcome of this study was the impact of CCT on a memory composite score, assessed through the Seoul Verbal Learning Test (SVLT) and Rey–Osterrieth Complex Figure Test (RCFT) visual memory test, which both included immediate recall, delayed recall after 20 min, and recognition. ³¹

Secondary outcomes

The secondary outcomes were the effect of CCT on comprehensive cognition, non‐cognitive symptoms, and functional connectivity (FC) in the resting brain related to the memory domain.

Global cognition was evaluated using the MMSE and MoCA, while comprehensive cognition was measured using Seoul Neuropsychological Screening Battery. ³¹ Composite scores for four domains were assessed and presented as age‐ and education‐adjusted Z‐scores: Attention was measured using the digit span forward and backward test ³¹ ; language ability was assessed using tests for language comprehension, repetition, and the Korean version of the Boston Naming Test (K‐BNT) ³² ; visuospatial function was evaluated using the clock drawing test and the RCFT copy task ³³ ; frontal executive function was evaluated using the go/no‐go test, digit symbol coding test, phonemic word fluency testing, the Trail Making Test‐B, and the Stroop colour reading test. ³¹

Non‐cognitive psychiatric symptoms that typically start to decline in the early stage of dementia were evaluated using validated scales. Depressive symptoms were assessed using the validated 30‐item Geriatric Depression Scale (GDS). ³⁴ , ³⁵ Higher scores on the GDS indicate more severe depression. Apathy was evaluated using the Korean version of Apathy Evaluation Scale (K‐AES), rated on a 4‐point Likert scale, with lower scores indicating more severe apathy. ³⁶ , ³⁷ The Positive and Negative Affect Schedule (PANAS) was used to assess affect, with 18‐items rated on a 5‐point Likert scale, yielding a positive affect score (PANAS‐P) and a negative affect score (PANAS‐N), with higher scores indicating higher affect. ³⁸ , ³⁹ The Quality of Life‐Alzheimer's Disease (QoL‐AD) scale, with 13 items rated on a 4‐point Likert scale, with higher scores indicating better quality, was used to evaluate participants' life quality. ⁴⁰ , ⁴¹

We also investigated the impact of CCT on the FC in the resting brain region related to memory functioning, which is noted later in the rsfMRI analyses section.

Usability of the CCT program

The People At the Center of Mobile Application Development (PACMAD) model assessed the usability of the CCT program, covering effectiveness, efficiency, satisfactory‐text size, satisfactory‐text type, learnability, memorability, errors, and cognitive loads. ⁴² However, the cognitive load item was not assessed because it was originally included in the evaluation of errors while using mobile apps when walking, while the CCT in this study was conducted in a seated position. Each of the seven items was rated on a Likert scale ranging from 1 (very low) to 5 (very high).

To evaluate motivation and engagement, the level of interest and satisfaction were evaluated post‐intervention using a visual analogue scale ranging from 0 to 100.

MRI acquisition

Participants underwent approximately 20 min of rsfMRI before and after the intervention, under the guidance of a radiographer. They were instructed to remain awake and relaxed while lying still in the scanner. A 3‐Tesla whole‐body Siemens scanner (TrioTim syngo; Siemens, Erlangen, Germany) was used to acquire functional images with an interleaved T2*‐weighted echo‐planar imaging gradient echo sequence (repetition time/echo time = 2500 ms/25 ms; flip angle = 90°; slice thickness = 3.5 mm; in‐plane resolution = 3.5 × 3.5 mm; matrix size = 64 × 64) using a 12‐channel birdcage head coil. For each participant, 160 functional volumes were acquired at both pre‐ and post‐training time points. After the fMRI, an anatomical image was acquired using a high, T1‐weighted, 3D gradient echo pulse sequence with magnetization prepared rapid gradient‐echo (repetition time/echo time/inversion time = 1900 ms/3.3 ms/900 m; flip angle = 9°; slice thickness = 1.0 mm, in‐plane resolution = 0.5 × 0.5 mm; matrix size = 416 × 512). T1‐weighted images were acquired only at the pre‐training time point.

rsfMRI FC analyses

Preprocessing of the rsfMRI data was performed using Statistical Parametric Mapping software version 12 (Wellcome Trust Centre for Neuroimaging; London, UK). First, a slice‐timing correction was applied and the centre of each image was relocated near the anterior commissure; then, rsfMRI and T1‐weighted images were imported into the CONN FC toolbox v19c for further preprocessing. To correct for between‐scan rigid body motion, the functional images were realigned to the first image in the time series. The functional images were co‐registered with anatomical images and spatially normalized to the Montreal Neurological Institute space using a transformation matrix derived from the T1‐weighted anatomical image segmentation. The functional images were then resliced to 2 × 2 × 2 mm and spatially smoothed using an 8 mm full width at half maximum Gaussian kernel.

All preprocessed fMRI images were band‐pass filtered (0.008–0.09 Hz), and physiological and other spurious noise sources in the blood oxygenation level‐dependent signal were removed using the anatomical component‐based noise correction strategy implemented in CONN. Outliers were calculated using the Artefact Detection Tools toolbox, ⁴³ and six motion correction parameters obtained from realignment were also modelled as nuisance covariates. The seed‐to‐voxel analyses were performed with the memory‐related seed regions, hippocampus, amygdala, and medial temporal region, with predefined regions of interest based on the Harvard‐Oxford atlas (FMRIB Software Library, Oxford, UK). Seed‐based analyses were adjusted for various demographic and clinical variables, including age, sex, years of education, vision and hearing state, smoking, alcohol consumption, history of depression and traumatic brain injury, family history of dementia, MBI score, apathy, and pharmacotherapy for prevention of dementia. The mean time series for each seed region was calculated and then correlated with the time courses of all other voxels in the brain for each participant.

Sample calculation

The sample calculation was based on a recent meta‐analysis that examined the effectiveness of CCT for people with MCI. ⁴⁴ The meta‐analysis utilized a random‐effects model and found medium effect sizes (standardized mean difference = 0.54 for global cognition) in 1059 participants across 18 different randomized controlled trials. Assuming an attrition rate of 20%, a total sample size of 26 patients (13 per treatment group) would yield a power of 0.8, with a two‐sided alpha error of 0.05, and a correlation of 0.7 among repeated measures. Power analysis was conducted using G*Power software version 3.1.9.2.

Statistical analyses

Comparisons of demographic and clinical variables between the two groups were analysed using the Mann–Whitney U test and χ² test. To determine the effect of CCT compared to educational book reading, repeated measure analysis of covariance was used. Confounding variables such as age, sex, years of education, vision and hearing state, smoking, alcohol consumption, history of depression and traumatic brain injury, family history of dementia, MBI score, apathy, and pharmacotherapy for prevention of dementia (e.g., choline alfoscerate and ginkgo biloba) were adjusted. Age and years of education were not adjusted in analyses that included comprehensive neuropsychological test results, which were presented as age‐ and years of education‐adjusted Z‐scores. All statistical analyses were performed using SPSS software version 23 (SPSS Inc., Chicago, Il, USA), with a significance level of P < 0.05 (two‐tailed).

For rsfMRI data, Pearson's correlation coefficients were transformed into normally distributed scores using the Fisher's r‐to‐z transformation. Group‐level comparisons between the CCT and control groups were conducted using a general linear model in which improved cognitive task score was the explanatory variable, and the post‐training minus pre‐training z‐transformation value was the dependent variable, after adjusting for age, sex, years of education, vision and hearing state, smoking, alcohol consumption, history of depression and traumatic brain injury, family history of dementia, MBI score, apathy, and pharmacotherapy for prevention of dementia. The statistical thresholds for significance were set at voxel‐wise uncorrected P < 0.001 and cluster‐wise corrected P < 0.05 to correct for false positive rates.

RESULTS

Participants

Of the 29 initially assigned participants (CCT: n = 15; control: n = 14), 27 participants completed the study, with two dropouts from the control group due to medical issues and personal reasons. Ultimately, 27 participants were included in the analyses. The trial flow chart is presented in Figure 1.

Figure 1.

Trial flow chart. CCT, computerized cognitive training.

Demographic and clinical characteristics

Of the 27 individuals, 15 (52%) and 12 (48%) were assigned to the CCT and control groups, respectively. The mean age was 74.36 ± 6.73 (CCT) and 75.08 ± 4.52 (control). Baseline evaluations did not differ significantly between groups except for hearing status (Table 1).

Table 1.

Demographics and clinical characteristics of the study population

Variables	CCT (n = 15)	Control (n = 12)	Z or χ2	P
Age (year)	74.36 ± 6.73	75.08 ± 4.52	−0.07	0.94
Sex (female, n)	8 (57.1%)	8 (61.5%)	0.05	0.82
Education (year)	8.00 ± 4.59	8.73 ± 4.45	−0.42	0.69
MMSE	23.57 ± 3.25	23.69 ± 3.61	−0.05	0.98
CDR	0.61 ± 0.29	0.62 ± 0.22	0.00	>0.99
CDR‐SOB	2.36 ± 1.62	2.46 ± 1.80	−0.07	0.94
B‐ADL	20.00 ± 0.00	20.00 ± 0.00	0.00	>0.99
K‐IADL	1.60 ± 4.16	1.27 ± 2.05	−0.12	0.91
MBI score	8.79 ± 4.16	11.77 ± 12.33	−0.22	0.83
Alcohol consumption	0.64 ± 0.74	0.54 ± 0.88	−0.61	0.62
Smoking	0.33 ± 0.49	0.25 ± 0.45	−0.46	0.72
Vision state	1.79 ± 0.70	1.54 ± 0.78	−1.02	0.35
Hearing state	1.00 ± 0.00	1.67 ± 0.89	−2.01	0.01
History of depression	6 (40%)	6 (50%)	0.27	0.60
History of TBI	2 (13.3%)	1 (8.3%)	0.17	>0.99
Pharmacotherapy for prevention of dementia	2 (13.3%)	2 (16.7%)	0.06	>0.99
Family history of dementia	5 (35.7%)	7 (53.8%)	0.90	0.34

Note: Data are presented as mean ± standard deviation or number (%). Mann–Whitney test was used except for sex, history of depression, pharmacotherapy for prevention of dementia, and family history of dementia for which the chi‐squared test was used. Alcohol consumption, smoking, vision and hearing impairment are scored on a Likert scale ranging from 1 (mild) to 3 (severe).

Abbreviations: CCT, computerized cognitive training; MMSE, Mini‐Mental State Examination; CDR, Clinical Dementia Rating; CDR‐SOB, Clinical Dementia Rating–Sum of Boxes; B‐ADL, Barthel Activities of Daily Living; K‐IADL, Korean version of Instrumental Activities of Daily Living; MBI, Mild Behavioural Impairment; TBI, traumatic brain injury.

Effect of CCT in memory functioning

CCT significantly improved the memory domain score (t = −2.19, P = 0.046), whereas educational reading did not (t = −1.27, P = 0.23) in within‐group comparisons. A group × time interaction favoured the CCT group (F = 5.87, P = 0.03) in Model II adjusted for confounding factors, indicating the CCT group had better memory improvement (Table 2).

Table 2.

Effect of CCT in memory functioning

Within‐group memory comparison	CCT (n = 15)	Control (n = 12)
Pre‐intervention memory score	−2.50 ± 1.91	−2.05 ± 1.60
Post‐intervention memory score	−1.92 ± 2.22	−1.56 ± 1.99
t, P	−2.19, 0.046 †	−1.27, 0.23

Between‐group intervention effect	Model I	Model II
Time effect (F, P, η 2)	5.65, 0.03 † , 0.18	0.81, 0.39, 0.06
Group effect (F, P, η 2)	0.55, 0.47, 0.02	7.27, 0.02 † , 0.36
Group × Time effect (F, P, η 2)	0.08, 0.77, 0.00	5.87, 0.03 † , 0.31

Note: Data are presented as mean ± standard deviation. Memory scores are Z‐scores adjusted for age and years of education. Paired t‐test was used for within group comparison and repeated measure analysis of covariance was used for between‐group intervention effect. Model I: no adjusted factors. Model II: adjusted for confounding factors including age, sex, vision and hearing state, smoking, alcohol consumption, history of depression and traumatic brain injury, family history of dementia, mild behavioural impairment score, apathy, and pharmacotherapy for prevention of dementia.

Abbreviation: CCT, computerized cognitive training.

^† Significant.

Effects of the CCT in other cognitive and non‐cognitive symptoms

Both groups showed within‐group improvement in frontal executive function (t = −2.91, P = 0.01 in CCT; t = −2.66, P = 0.02 in control) (Table 3). Non‐cognitive symptoms improved in the CCT group for the K‐AES (t = −4.50, P = 0.001) and QoL‐AD scale (t = −2.48, P = 0.03), and in the control group for PANAS‐N (t = 2.41, P = 0.04) and K‐AES (t = −3.06, P = 0.01) (Table 3). Although CCT improved apathy (F = 4.69, P = 0.04) compared to control group in Model I, CCT's effects on cognition and psychiatric symptoms were not significantly different from the control group after adjusting for confounders in Model II (Table 4).

Table 3.

Within‐group comparison of the cognition and psychiatric symptoms before and after interventions

	CCT group (n = 15)			Educational book reading group (n = 12)
Variables	Pre	Post	t or Z, P	Pre	Post	t, P
Global cognition
MMSE	23.07 ± 3.69	24.13 ± 3.70	−1.89, 0.08	23.67 ± 3.77	24.33 ± 3.08	−1.34, 0.21
MoCA	17.73 ± 6.14	19.07 ± 4.30	−1.67, 0.12	18.25 ± 4.86	18.58 ± 5.04	−0.72, 0.49
Cognitive function
Attention	−0.40 ± 1.11	−0.55 ± 0.97	0.92, 0.38	−0.96 ± 1.01	−0.91 ± 0.51	−0.28, 0.79
Language	−0.89 ± 2.62	0.01 ± 1.19	−1.17, 0.26	−0.80 ± 2.84	−0.35 ± 2.01	−1.41, 0.19
Visuospatial	−1.21 ± 2.27	−0.89 ± 1.90	−1.13, 0.28	−1.23 ± 1.45	−0.63 ± 1.87	−1.90, 0.08
Frontal executive	−1.44 ± 1.64	−1.23 ± 1.61	−2.91, 0.01 †	−1.67 ± 1.57	−1.21 ± 1.34	−2.66, 0.02 †
Non‐cognitive symptoms
PANAS‐P	19.80 ± 6.57	23.27 ± 5.46	−1.62, 0.13	21.33 ± 3.65	21.92 ± 3.37	−0.38, 0.72
PANAS‐N	16.47 ± 5.48	16.67 ± 6.00	−0.13, 0.90	17.42 ± 3.50	14.67 ± 3.28	2.41, 0.04 †
K‐AES	40.60 ± 7.10	50.53 ± 8.28	−4.50, 0.001 †	43.58 ± 7.99	47.58 ± 8.07	−3.06, 0.01 †
GDS	12.71 ± 7.00	10.93 ± 7.24	0.98, 0.35	11.08 ± 4.96	10.00 ± 4.99	0.99, 0.34
QoL‐AD	27.93 ± 5.75	32.73 ± 9.15	−2.48, 0.03 †	30.25 ± 4.85	31.67 ± 6.20	−1.45, 0.18

Note: Data are presented as mean ± standard deviation. Cognitive function tests are Z‐scores adjusted for age and years of education. Paired t‐test was used for within‐group comparison, except for Mann–Whitney test for variables without normal distribution (language and visuospatial function).

Abbreviations: CCT, computerized cognitive training; MMSE, Mini‐Mental State Examination; MoCA, Montreal Cognitive Assessment; PANAS‐P, Positive And Negative Affect Schedule‐positive affect; PANAS‐N, Positive And Negative Affect Schedule‐negative affect; K‐AES, Korean version of Apathy Evaluation Scale; GDS, Geriatric Depression Scale; QoL‐AD, Quality of Life‐Alzheimer's Disease.

^† Significant.

Table 4.

Effect of CCT compared to control in cognitive function and psychiatric symptoms (n = 27)

	Model I			Model II
	Time	Group	Group × Time	Time	Group	Group × Time
Variables	F, P, η 2	F, P, η 2	F, P, η 2	F, P, η 2	F, P, η 2	F, P, η 2
Global cognition
MMSE	5.03, 0.034 † , 0.17	0.09, 0.77, 0.00	0.27, 0.61, 0.01	0.75, 0.40, 0.06	3.44, 0.09, 0.24	1.33, 0.27, 0.11
MoCA	2.86, 0.103, 0.10	0.00, 0.99, 0.00	1.03, 0.32, 0.04	0.01, 0.92, 0.00	1.57, 0.24, 0.13	0.39, 0.54, 0.03
Cognitive function
Attention	0.20, 0.659, 0.01	1.76, 0.20, 0.07	0.90, 0.41, 0.03	0.06, 0.81, 0.01	0.31, 0.59, 0.02	1.72, 0.21, 0.12
Language	4.22, 0.051, 0.14	0.15, 0.71, 0.01	0.00, 0.99, 0.00	0.36, 0.56, 0.03	0.02, 0.89, 0.00	0.00, 0.98, 0.00
Visuospatial	1.49, 0.234, 0.06	0.40, 0.54, 0.02	0.58, 0.46, 0.02	0.52, 0.49, 0.04	1.95, 0.19, 0.13	1.40, 0.26, 0.10
Frontal executive	1.49, 0.234, 0.06	0.40, 0.54, 0.02	0.58, 0.46, 0.02	0.15, 0.71, 0.01	0.40, 0.54, 0.03	0.33, 0.58, 0.03
Non‐cognitive symptoms
PANAS‐P	2.14, 0.156, 0.08	0.00, 0.95, 0.00	1.08, 0.31, 0.04	0.00, 0.98, 0.00	0.12, 0.73, 0.01	0.70, 0.42, 0.06
PANAS‐N	1.60, 0.218, 0.06	0.11, 0.74, 0.00	2.14, 0.16, 0.08	0.53, 0.48, 0.05	0.02, 0.88, 0.00	1.39, 0.26, 0.11
K‐AES	25.87, <0.001 † , 0.51	0.00, >0.99, 0.00	4.69, 0.04 † , 0.16	2.39, 0.15, 0.17	1.28, 0.28, 0.10	2.53, 0.14, 0.17
GDS	1.68, 0.208, 0.07	0.34, 0.56, 0.01	0.10, 0.75, 0.00	0.01, 0.94, 0.00	0.94, 0.35, 0.09	0.15, 0.71, 0.02
QoL‐AD	7.05, 0.014, 0.22	0.07, 0.79, 0.00	2.09, 0.16, 0.08	0.01, 0.94, 0.00	0.14, 0.72, 0.01	0.51, 0.49, 0.04

Note: Data are presented as mean ± standard deviation. Cognitive function tests are Z‐scores adjusted for age and years of education. Repeated measure analysis of covariance was used for between‐group comparison after log‐transformation for variables without normal distribution (language and visuospatial function). Model I: no adjusted factors. Model II: adjusted for confounding factors including age, sex, vision and hearing state, smoking, alcohol consumption, history of depression and traumatic brain injury, family history of dementia, mild behavioural impairment score, apathy, and pharmacotherapy for prevention of dementia.

Abbreviations: CCT, computerized cognitive training; MMSE, Mini‐Mental State Examination; MoCA, Montreal Cognitive Assessment; PANAS‐P, Positive And Negative Affect Schedule‐positive affect; PANAS‐N, Positive And Negative Affect Schedule‐negative affect; K‐AES, Korean version of Apathy Evaluation Scale; GDS, Geriatric Depression Scale; QoL‐AD, Quality of Life‐Alzheimer's Disease.

^† Significant.

Usability, interest, and satisfaction

The PACMAD model demonstrated acceptable usability across all seven categories, with the highest score being in the satisfaction‐text size (4.27 ± 0.88) and the lowest score being in the errors (3.87 ± 0.74). Overall, the CCT program showed acceptable usability across PACMAD categories, with participant ratings higher than researchers' ratings (Table S3 in the supplemental data). The level of interest (84.00 ± 15.38) and satisfaction (90.13 ± 11.19) were similar between the participants and researchers.

Increased functional connectivity in fMRI

We investigated changes in the FC in the hippocampus, amygdala, and medial temporal region, and identified increased networks based on the hippocampus and temporal fusiform gyrus (Table S4 in the supplemental data). Figure 2 illustrates the increased regional FC calculated in association with the memory improvements in the CCT group, compared to the control group.

Figure 2.

Increased brain connectivity related to memory improvement in the CCT group compared to the control group. Increased functional connectivity, based on both hippocampus (A) and temporal fusiform gyrus (B), associated with memory improvement in the CCT group compared to the control group. Seed‐to‐voxel analyses were performed after adjusting for age, sex, years of education, vision and hearing state, smoking, alcohol consumption, history of depression and traumatic brain injury, family history of dementia, mild behavioural impairment score, apathy, and pharmacotherapy for prevention of dementia with significance of voxel‐wise uncorrected P < 0.001 and cluster‐wise false discovery rate‐corrected P < 0.05. CCT, computerized cognitive training.

DISCUSSION

This study aimed to examine the transfer effect of non‐memory CCT on memory functioning and neural connectivity in patients with MCI. This study secondarily aimed to find the effect of CCT on overall cognitive and non‐cognitive symptoms. The results revealed significant between‐group memory improvement in the CCT group compared to the control group. This effect was attributed to the increased FC based on the memory‐related brain regions such as the hippocampus and medial temporal regions. Overall, these results suggest that the transfer effect of multidomain CCT was prominent on the memory domain and functional neural plasticity even when memory was not trained explicitly.

The main finding of this study is the significant transfer effect of multidomain CCT on the memory domain when memory was not trained. One of the primary goals of CCT is to achieve transfer effects, which can be observed at multiple levels. ⁴⁵ These include near transfer, which indicates that the trained task improves other non‐trained task within the same cognitive domain, and far transfer, which refers to the effect on non‐trained tasks in other domains and in global cognitive ability. ⁴⁵ Our multidomain CCT program was designed to include four distinctive domains—attention, language, visuospatial function, and executive function—with no explicit or implicit memory training. To investigate a far‐transfer effect on the memory domain, the subtasks in our program were aimed at training sustained/selective/divided attention, processing speed, and planning/reasoning/organization, tasks that require simultaneous metacognitive activities without a memory component. Based on age‐related changes in frontal lobe reserve, working memory and executive function are largely responsible for general age‐related cognitive decline. ⁴⁶ Our CCT program might have utilized a compensatory mechanism for effect generalization from executive function, reasoning ability, and fluid cognition to memory functioning in its enriched environmental nature, which is far transfer, even compared with an active control group that read educational books and answered review questions about the contents in a learning‐based approach multiple times in each session. This is in line with previous reports that memory improvement has the largest effect sizes. ⁴⁴ , ⁴⁷ , ⁴⁸ The CCT and control groups both showed improvements in frontal executive function, but only the CCT group showed memory improvement, even without memory training. This result is the first to find the far‐transfer effect on an untrained domain which may imply that the memory domain could be the primary beneficiary of multidomain CCT.

The exploratory aim of this study was to investigate the increased functional network based on the memory‐related regions including the hippocampus, amygdala, and medial temporal region. We discovered enhancement in the hippocampal‐frontal network, which is consistent with previous studies that reported multidomain CCT as improving the network between the hippocampus and superior frontal lobe, which is related to memory ability. ⁴⁸ The temporal region is the major mediator of memory functioning that degrades with aging and MCI, particularly connected to the frontal region. ⁴⁹ The CCT in this study might have strengthened the frontal‐hippocampal network involving a memory transfer effect and this may represent a unique mechanism of CCT that can delay cognitive decline. ⁵⁰ Additionally, we found memory‐related functional enhancements in the fusiform network, reaching to the occipital regions. This result may be due to the increased visual processing and perceptual stimulus that were repeated in the CCT compared to the control intervention. The temporo‐occipital network has been found to regulate visual memory encoding, facial recognition, and visuo‐perceptual working memory. ⁵¹ , ⁵² A previous study found that amnestic MCI patients have increased FC in this network, which may indicate an attempt to overcome neurodegenerative changes. ⁵³ Also, the strengthening of this network after CCT is consistent with compensational evidence in individuals with subjective cognitive decline. ⁵⁴

Another aspect of the results is that CCT was effective on cognitive function in MCI. There has been a consistent accumulation of literature on the effect of CCT in healthy older adults, patients with MCI, and those with mild to moderate dementia over the past two decades. Representative meta‐analyses have demonstrated the overall positive effects of cognitive training, including CCT, in older adults and patients with mild to moderate dementia, but not in patients with MCI. ⁹ , ¹⁰ , ¹² However, other meta‐analyses have reported small to moderate effects of CCT in MCI patients, with broader eligibility criteria for study selection. ¹¹ , ⁴⁷ , ⁵⁵ The most recent and largest study, which included 18 studies with 1059 participants with MCI, demonstrated that CCT improved global cognition, executive function, working memory, and episodic memory. ⁴⁴ Another meta‐analysis that employed strict eligibility criteria for individuals diagnosed only with MCI demonstrated that CCT had an effect on memory, working memory, and global cognition, but did not significantly affect executive function. ⁴⁷ In our results, within‐group improvement in memory and frontal executive function disappeared in between‐group comparisons except for memory. This might be explained by the small number of participants and a slightly shorter duration of 8 weeks in this study compared to previous studies that showed mean trial duration of 10.5 weeks. ⁴⁴ However, the results of this study showing improvement in memory alone is comparable to the results of existing studies in which memory showed the greatest improvement. ⁴⁴ , ⁴⁷ , ⁴⁸

Non‐cognitive and psychiatric symptoms were evaluated as secondary outcomes in this study. Within‐group improvements were found in apathy and QoL in the CCT group, and in negative affect and apathy in the control group. However, there was no superior effect of CCT compared to the control group after adjusting for covariates. Since cognitive and depressive symptoms often co‐occur, CCT has been reported to be effective in depressive disorders. ⁵⁶ Also, virtual reality cognitive training has been found to be effective in psychiatric symptoms. ⁵⁷ , ⁵⁸ However, the lack of a group difference in our study may be due to the small sample size and relatively higher GDS score, which could hinder the generalizability although we adjusted for depressive symptoms.

The usability evaluation showed modest to good user experiences. The PACMAD model applied in this study was originally designed to assess how quickly and easily people can use mobile devices in the industry field. ⁴² The result showed satisfactory usability of the CCT in MCI participants. User evaluation was ‘moderate’ to ‘high’, while researchers evaluated all seven items as ‘moderate’. This better‐than‐expected user experience with CCT is in line with a previous review that showed positive user experiences with CCT among older people with cognitive decline, ⁵⁹ even though they require more time and effort to complete the tasks. Participants and researchers both demonstrated satisfaction and interest scores exceeding 80 out of 100, indicating high engagement levels in activities that sustain an individual's interest and motivation. ⁶⁰ Overall, this study suggests that the usability, interest, and satisfaction is appropriate and can facilitate CCT without overwhelming novelty or complexity.

This study has several limitations. The small sample size compromises statistical power, despite our sample size calculations indicating adequacy based on a recent meta‐analysis. Exclusion of two participants who did not complete the training may bias results. Generalizability is limited as participants were recruited solely from memory clinics. Additionally, the absence of AD biomarker data in MCI patients may increase heterogeneity, and unblinded randomization could impact results.

CONCLUSION

Non‐memory CCT demonstrated transfer effects on memory function in MCI patients compared to reading educational books, associated with hippocampal and medial temporal network activity. However, further large‐scale studies are required to fully assess these effects on both a short‐ and long‐term basis. Aging populations and immersive technology advancements will pose new challenges for CCT, including content determination, delivery methods, control groups, and adherence. Collaboration among medical professionals, researchers, and experts from various fields is essential for conducting clinical research on computerized therapies for patients with cognitive decline.

DISCLOSURE

All authors declare no conflict of interests for this article.

TRIAL REGISTRATION

This study is registered on the Korean Clinical Research Information Service, which is a World Health Organization recognized primary registry (KCT0009281). Registered on 19 March 29, 2024—retrospectively registered. https://cris.nih.go.kr/cris/search/detailSearch.do?seq=26549&status=1&seq_group=26549&search_page=M.

Supporting information

Data S1. Supporting Information.

DATA AVAILABILITY STATEMENT

An enhanced version of the CCT program is accessible online for free at https://play.google.com/store/apps/details?id=com.c2monster.LongLiveYouth&pcampaignid=web_share. The other data of this study are available from the corresponding authors upon reasonable request.