A new program for systematically enhancing cognitive reserve in healthy adults: A pilot randomized active-controlled clinical trial

Carol Kotliar; Lisandro Olmos; Martín Koretzky; Ricardo Jauregui; Tomás Delía; Oscar Cingolani

doi:10.1371/journal.pone.0331193

. 2025 Oct 1;20(10):e0331193. doi: 10.1371/journal.pone.0331193

A new program for systematically enhancing cognitive reserve in healthy adults: A pilot randomized active-controlled clinical trial

Carol Kotliar ^1,^2,^*, Lisandro Olmos ^1,^3,^#, Martín Koretzky ^1,^#, Ricardo Jauregui ^1,^#, Tomás Delía ^1,^#, Oscar Cingolani ^4,^#

Editor: Roya Khanmohammadi⁵

PMCID: PMC12488004 PMID: 41032503

Abstract

Objective

To evaluate the effectiveness of the Mental Training Tech 24.5 (MTT24.5) cognitive stimulation program, designed to enhance cognitive performance and neuroplasticity in healthy adults.

Background

Cognitive decline is a significant concern in aging populations, with research suggesting that neuroplasticity and cognitive reserve can be enhanced through targeted cognitive training. The MTT24.5 program aims to stimulate brain function through a combination of new knowledge acquisition (DATA) and learning techniques (TECHS), organized into a systematic algorithm. This approach may offer a novel way to prevent or mitigate age-related cognitive decline.

Design

Pilot clinical study, active-controlled, open randomization.

Setting

Adults from the general population with no clinical cognitive deterioration, recruited from three sites within the Autonomous City of Buenos Aires and its metropolitan area.

Participants

120 volunteers were enrolled, of which 76 participants (56 in the intervention group, 20 in the control group) met the study requirements and selected a site closest to their residence.

Methods

The MTT24.5 program consists of 12 weekly in-person sessions (totaling 24.5 hours), during which participants learned 40 knowledge units (DATA) and 100 learning techniques (TECHS). These were organized into binomials, where each unit of DATA was paired with 3–4 TECHS. Pre- and post-intervention assessments included medical history, lifestyle factors, cognitive reserve scale, Addenbrooke’s Cognitive Examination-Revised (ACE-R), and Mini-Mental State Examination (MMSE).

Results

The mean age was 59 years for both groups. Baseline ACE-R scores were comparable (91.3). The global cognitive score increased by 4.6 points (5%) in the intervention group compared to a decrease of 0.5 points in the control group (p < 0.001). The most significant improvement was observed in the memory domain (2.4 points, 11.4% increase) versus a 0.3-point increase in the control group (p < 0.007), with secondary improvements in verbal fluency, language, and visuospatial skills. Notably, participants with baseline ACE-R scores below 85 showed greater improvements (p < 0.003). The effects were consistent across various phenotypic factors, such as age, sex, chronic disease distribution, and lifestyle.

Conclusions

The MTT24.5 program, based on a systematic algorithm for acquiring new knowledge and skills, significantly enhances cognitive reserve and overall cognitive performance, particularly in individuals with lower baseline cognitive scores. These findings suggest that structured cognitive stimulation could play a critical role in preventing cognitive decline and promoting cognitive health in healthy adults. Given the promising results, future studies involving larger populations and long-term follow-up are essential to validate these effects and explore the potential for mitigating age-related cognitive decline and enhancing quality of life.

Registration

The study was registered in accordance with local regulations at the National Council for Scientific and Technological Research (CONICET) – Institute of Biomedical Research (BIOMED), and also in the National Ethics Committee, and at clinicaltrials.gov (NCT06549517).

Introduction

As global life expectancy continues to rise [1–3], the need for effective strategies to enhance cognitive reserve throughout the lifespan has become increasingly important. The key cognitive functions that sustain an autonomously functioning life include attention, memory, verbal fluency, language, and visuospatial skills [4–6]. Efforts to sustain and enhance them throughout life can promote neuroplasticity [7,8], thereby strengthening cognitive reserve [9], with factors such as age, experience, and environment modulating this adaptive brain process [10,11]. However, most interventions aimed at promoting cognitive function and neuroplasticity have primarily focused on older adults already experiencing cognitive decline [12–15]. A truly transformative approach would advocate for the integration of continuous brain training strategies throughout the lifespan, even in cognitively healthy adults without clinical signs of cognitive deterioration. By progressively and sustainably enhancing cognitive reserve through novel strategies, such an approach could potentially prevent, delay, or reduce age-related cognitive decline.

There have been novel studies such as Hardy et al [16] that sustain the benefits of interactive platforms such as Lumosity which aimed, and succeeded to, demonstrate that progressively challenging, targeted cognitive training can be an effective tool for improving core cognitive abilities including speed of processing, working memory, and fluid reasoning. The results there presented are a solid demonstration that cognitive training programs targeting a variety of cognitive capacities witch different exercises can be more effective than traditional activities such as crossword puzzles and Sudoku at improving a broad range of cognitive abilities.

The Nun Study, led by epidemiologist David Snowdon, investigated the cognitive health of 678 nuns who remained intellectually active throughout their lives [17]. They were regularly engaged in studying, teaching, and other cognitively demanding activities, with their cognitive test scores remaining normal and stable until their deaths. Postmortem examinations of their brains revealed significant neuropathological markers consistent with Alzheimer’s disease, including neurofibrillary tangles and amyloid plaques [18]. Despite the presence of these pathological changes, none of the participants exhibited clinical signs of dementia. These findings suggest that lifelong intellectual engagement contributed to the development of a substantial cognitive reserve, which may have played a protective role, allowing the brain to compensate for the neuropathological burden of Alzheimer’s disease and thereby preserve cognitive function. This underscores the potential of continuous cognitive stimulation in mitigating the clinical manifestations of neurodegeneration.[19] Similarly, research on London taxi drivers has shown that extensive spatial navigation training leads to structural brain changes [20]. These drivers undergo rigorous training, which involves memorizing the names and layouts of over 25,000 streets and thousands of points of interest in London. Functional magnetic resonance imaging (fMRI) studies have revealed that this intensive spatial navigation expertise is associated with increased gray matter volume in the posterior hippocampus, a brain region crucial for memory and spatial navigation [19]. Furthermore, the amount of navigation experience correlates with hippocampal gray matter volume, suggesting that spatial knowledge and experience are directly linked to structural brain changes [20,21]. Lessons from the Nun and Taxi Driver studies demonstrate that interventions introducing novel learning experiences and the acquisition of new skills provide a more robust stimulus for neuroplasticity. In contrast, many existing cognitive stimulation programs focus on re-training skills already acquired, often through the reinforcement of familiar knowledge and memory, which may offer less stimulation for brain adaptation and plasticity [22–25].

Our new program, Mental Training Tech 24.5 (MTT24.5), is based on a structured system of brief learning sessions encompassing the four basic sciences, with no interrelated connections between them, aiming to stimulate cognitive reserve through diverse brain areas. This approach incorporates memory techniques, including the use of codes and braille literacy [26,27], as well as activities targeting the non-dominant hemisphere of the brain [28]. With a panel of 100 distinct tasks, the program is designed to challenge participants with new and unfamiliar material, thereby promoting neuroplastic changes.

Notably, the study focuses on cognitively healthy adults without clinical signs of cognitive impairment, distinguishing it from previous studies that have primarily involved individuals with cognitive decline [12–15]. This clinical trial represents the general population, with typical rates of chronic non-communicable diseases [29], offering a valuable opportunity to evaluate the broader applicability of this cognitive training methodology.

Through this pilot design, we aim to develop a hypothesis to validate the effectiveness of the MTT24.5 ‘s cognitive learning interventions for improving cognitive performance in healthy adults. Future studies could expand on this work by correlating the effects with long-term follow-up throughout the lifespan, with the goal of analyzing its potential impact on the reduction or delay of age-associated cognitive decline risk.

Objectives

Primary objective: to assess the cognitive effects of MTT24.5 in global cognitive performance among healthy adults. Secondary objective: to evaluate effects of MTT24.5 in cognitive domains of memory, attention, verbal fluency, language, and visuospatial skills in these population.

Methods

Design

This is a randomized, controlled, open-label trial involving 76 healthy middle-aged adults. Participants were randomly assigned in a 2:1 allocation ratio to two groups: an intervention group that completed the cognitive stimulation program (n = 56) and a control group (n = 20) (Fig 1).

Fig 1 — This diagram illustrates the flow of participants throughout the study, from initial screening to final analysis. A total of 56 participants were randomly assigned to the MTT24.5 cognitive training program (intervention group), and 20 were assigned to the control group.

Participants attended 12 in-person sessions of the MTT24.5 cognitive stimulation program and were required to meet the following

1]
inclusion criteria: both sexes, aged 45–80 years, physical and mental autonomy for daily living; and
2]
exclusion criteria: no cognitive complaints or clinical manifestations of cognitive impairment, and no impairments in writing, hearing, or reading that would interfere with participation. Additionally, participants could not be taking medications affecting cognition or be enrolled in other cognitive intervention programs.

The recruitment period started on March 1 and concluded on October 1, 2023. The trial ended in December 2023, when the last participant completed their participation. There were not important changes to methods after trial commencement.

Randomization and allocation: the random allocation sequence was generated using a computer-based list of sequential numbers. The study used an open-label 2:1 randomization strategy.

A 2:1 randomization ratio was choice to support recruitment and enhance adherence among healthy volunteers by increasing the likelihood of being assigned to the intervention group. In studies involving cognitive enhancement in healthy populations, such an approach can be particularly effective in motivating participation. Given the nature of this pilot study, a larger sample size in the intervention arm allowed for a more informative preliminary assessment of feasibility and potential effects. This decision was made after careful consideration of ethical principles, study objectives, and available resources, ensuring a scientifically valid comparison between group.

Participants were assigned to either the intervention or control group in a 2:1 ratio, with blocks of three. Each block consisted of two participants allocated to the intervention group and one to the control group, ensuring that the allocation ratio was maintained. The allocation sequence was concealed by an independent researcher who was blinded to the characteristics of the participants. Volunteers were contacted in a sequential manner, and as each volunteer agreed to participate, the intervention assignment was revealed.

Those who fulfilled study requirements was invited to select a site for the in-person training sessions closest to their residence (2 sites located within the Autonomous City of Buenos Aires and 1 site in the northern metropolitan area). The data for each participant were anonymized and collected by a researcher authorized by the Research and Ethics Committee as coded data entry for subsequent analysis.

Ethics statement and informed consent

The study was approved by the Institutional Review Board and the Local Ethics Committee. All participants provided written informed consent to be included. The study was registered in accordance with local regulations at the National Council for Scientific and Technological Research (CONICET) – Institute of Biomedical Research (BIOMED), as well as a surrogate nationally Ethics Committee. an at clinicaltrials.gov: NCT06549517 The study was registered on ClinicalTrials.gov (NCT-06549517) upon completion as the trial did not involve a clinical population. The authors confirm that all ongoing and related trials for this intervention are now registered.

Participants

A total of 76 participants were enrolled in the study, with 56 in the intervention group and 20 in the control group. One participant from the active group was discontinued because her attention deficit hyperactivity disorder (ADHD) had not been reported at the beginning. No participants were lost to follow-up, and therefore, no intention-to-treat analysis was necessary. The analysis was conducted according to the original assigned groups. The mean age of participants was 59 years in both groups, with a slight variation in standard deviation. Most participants in both groups were male (65.0% in the control and 63.6% in the intervention group). Sixty percent of the participants in the control group and 58.2% in the intervention group were aged ≤65 years. The intervention group had a slightly greater mean years of education (18.0 years) compared to the control group (16.4 years). The baseline Addenbrooke’s Cognitive Examination scores were comparable between the control (91.3) and the intervention group (91.3), indicating similar cognitive function at baseline. A small fraction of participants in the intervention group, less than 15% (n = 8), had a baseline ACE-R score of less than 85, although they did not report any cognitive complaints or show clinical manifestations of cognitive impairment in their daily life or autonomy. There were no substantial differences in clinical characteristics between the control and intervention groups. This cohort represents the general population, with typical prevalence of chronic non-communicable diseases (NCDs) such as diabetes, hypertension, and dyslipidemia Table 1.

Table 1. Baseline characteristics by group.

Socio-demographic characteristics	Control Group (N = 20)	Intervention Group (N = 55)
	n/N (%)	n/N (%)
Sex
Male	13/20 (65.0%)	35/55 (63.6%)
Female	7/20 (35.0%)	20/55 (36.4%)
Age*	58.9 (15.9)	58.9 (13.3)
Age categorized
<=65 years	12/20 (60.0%)	32/55 (58.2%)
> 65 years	8/20 (40.0%)	23/55 (41.8%)
Years of education*	16.4 (5.2)	18.0 (3.7)
Baseline ACE*	91.3 (4.9)	91.3 (6.2)
Baseline ACE categorized
<=85	2/20 (10.0%)	8/55 (14.5%)
> 85	18/20 (90.0%)	47/55 (85.5%)
Main Clinical Characteristics
Cognitive reserve
Low	9/20 (45.0%)	24/55 (43.6%)
High	11/20 (55.0%)	31/55 (56.4%)
Diabetes	3/20 (15.0%)	8/55 (14.5%)
Hypertension	8/20 (40.0%)	24/55 (43.6%)
Dyslipidemia	10/20 (50.0%)	31/55 (56.4%)
Dementia family history	5/20 (25.0%)	15/55 (27.3%)
Use of aspirin	5/20 (25.0%)	8/55 (14.5%)
Use of statins	6/20 (30.0%)	20/55 (36.4%)

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*Mean and (SD) was reported.

Intervention description

Mental Training Tech 24.5 (MTT24.5) is a cognitive enhancement program designed to strengthen cognitive reserve through a structured combination of novel knowledge units and multisensory instructional techniques. The program integrates two core components: (1) DATA, which represent discrete knowledge items, and (2) TECHS, which are techniques used to reinforce learning and support cognitive integration.

DATA (knowledge units): each DATA unit corresponds to a concise statement, no more than 15 words, representing a fact or concept derived from one of four major scientific domains: cultural, social, formal (including logic and mathematics), and biological sciences. These units are designed to be self-contained and not dependent on one another, allowing for independent cognitive engagement with each piece of content. The aim is to expose participants to knowledge that often lies outside their professional or personal expertise, thereby stimulating underused cognitive pathways. To support engagement and memory retention, each DATA unit is introduced with supplementary multimedia materials including short videos, illustrative images, contextual narratives, and emotionally engaging elements. A total of 40 DATA units are presented across the full course of the program,

TECH (learning techniques): each TECH refer to structured exercises designed to reinforce the learning of each DATA unit through tactile, visual, motor, and multisensory modalities. A pool of 100 TECHS was selected based on peer-reviewed evidence of their potential to stimulate neuroplasticity and enhance cognitive functioning in healthy adults from a literature review of 25 cognitive training studies published between 2000 and 2022 through search engines using terms such as “cognitive stimulation exercises,” “neuroplasticity,” “adult learning,” and “cognitive function” across MEDLINE (via PubMed), EMBASE, Cochrane Library, Web of Science, SCOPUS, LILACS, and Google Scholar.

Among the most frequently employed TECHS are:

Braille Literacy (used in ~60% of pairings): Participants learn to read and write in Braille, stimulating somatosensory and spatial processing areas of the brain [26,27].
Non-Dominant Handwriting: Tasks involving writing the DATA statement using the non-dominant hand to activate motor and executive control regions [28].
Mirrored Bilateral Writing: Simultaneous writing with both hands—left to right with the left hand and right to left with the right—designed to engage bilateral motor coordination and interhemispheric communication.
Multisensory Simulation: The TECHS vary in complexity and modality, some are unimodal, while others involve up to five concurrent modalities based on the evidence that multimodal stimulation enhances encoding and long-term retention. Participants could be asked to perform concurrent motor tasks (e.g., pressing a spring with one foot, moving an arm rhythmically) while decoding Braille written by another participant with closed eyes. This is intended to reinforce memory through sensorimotor integration [30].

An example of a data-tech pair is shown below:

DATA	TECHS
The oldest man to reach the summit of Mount Everest was the Japanese climber Yuichiro Miura, who achieved this at age 80.	(1). Write the phrase “MIURA EVEREST 80” using the non-dominant hand.
	(2). Simultaneously write “MIURA EVEREST 80” in mirrored form with both hands (left-to-right with the left hand, right-to-left with the right hand).
	(3). Write “MIURA EVEREST 80” using a Braille code tablet and stylus.
	(4). Write in Braille a word (4–8 letters) that represents an emotion or historical context related to the DATA (e.g., courage, snow, oldest, achievement), and pass the Braille sheet to another participant, who decodes it by touch with eyes closed.
	(5). During the trainer’s reading of statements about Miura, participants must continuously move both feet up and down while listening. When a statement is correct, they raise their non-dominant hand; if incorrect, they press a lighted button using their dominant hand.

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The association between each of the 40 DATA and its corresponding TECHS is predetermined and documented in the program’s patent to ensure reproducibility and minimize variability across participant groups.

Program delivery.

The MTT24.5 program is conducted in a presential classroom format over 12 weekly sessions totaling 24.5 instructional hours, with one certified trainer assigned to every 20 participants and additional assistants added as class size increases. Participants are required to attend at least 80% of the sessions to complete the program. The name “24.5” reflects this cumulative instructional time and draws from structures used in cognitive training studies such as the ACTIVE trial (Advanced Cognitive Training for Independent and Vital Elderly) [31]. Make-up sessions are available in case of absences to maintain program integrity and continuity of cognitive engagement.

In each class, an average of 3.5 DATA concepts are introduced, each paired with 3–4 TECHS following a standardized algorithmic format [DATA + TECHS] defined in the program’s patent to ensure consistent delivery across cohorts (Fig 2).

Fig 2 — The goal is the direct stimulation of neuroplasticity and cognitive reserve through new, systematized, and structured learning.

Evaluations

a)
Addenbrooke’s Cognitive Examination, ACE-R) [32] score: the ACE-R includes Mini-Mental State Examination (MMSE), and it contains a subset of tasks assessing general cognitive functioning, such as orientation, registration, attention, and recall. However, the ACE-R is more detailed and includes additional subtests for language, fluency, and visuospatial abilities, which are not fully covered by the MMS. The full revised version we used includes the MMSE and evaluation of different domains as memory, attention, language, and visuospatial skills abilities. Improvement in each cognitive ability outcome was assessed using the respective sub-dimensions of the ACE score, and the difference between post-intervention and pre-intervention sub-scores was computed. The ACE-R score ranges from 0 to 100.
b)
Cognitive reserve assessment-CRS: is a test that measures participation in cognitive stimulating activities throughout a person’s lifetime. Items included in the CRS assessment are scholarship, reading, playing instruments, collecting things, practicing other languages, among others [33].

Outcomes

The primary outcome of the study was the change in global cognitive ability.

Secondary outcomes were the change in Cognitive Specific Domains: Cognitive outcomes were assessed using the sub-dimensions of the ACE-III, including memory, attention, verbal fluency, language, and visuospatial skills. The change in each domain was calculated as the difference between post-intervention and pre-intervention sub-scores. The sub-score ranges are as follows: memory (0–26), attention (0–8), verbal fluency (0–14), language (0–16), and visuospatial skills (0–12). There were no changes to trial outcomes after the trial commenced.

Statistical analyses

Statistical plan: The study protocol, statistical analysis plan according CONSORT guidelines are available in the complementary file SAP.

Descriptive Statistics: Socio-demographic and clinical characteristics of participants were summarized using means and standard deviations (SD) for continuous variables, and frequencies and percentages for categorical variables.

A sample size of 75 subjects will provide a power of at least 80% to detect a minimum difference of 4 points in the score improvement between the two groups, assuming a maximum standard deviation of 5.4 points. This effect size of 0.80 used in our sample size calculation was based on prior literature, particularly the methodology and effect size interpretation used in the ACTIVE trial (Advanced Cognitive Training for Independent and Vital Elderly). Although the observed effects in ACTIVE ranged from small to moderate (e.g., 0.23 for reasoning and 0.66 for speed), we considered an effect size of 0.80 as a conservative target to detect a meaningful difference with sufficient power, assuming a best-case scenario for the intervention’s impact. Additionally, we considered the characteristics of our primary cognitive outcome measure. For example, in the Addenbrooke’s Cognitive Examination (ACE), a 1-point difference is clinically relevant for identifying cognitive decline. Therefore, assuming an intervention could achieve at least a moderate to large improvement (corresponding to 4 points, SD = 5.4, d = 0.8) was both clinically reasonable and consistent with previous literature on cognitive training effects.

Impact Assessment: The effect size was calculated as the difference in mean improvement between the intervention and control groups. Cohen’s d statistic was computed to determine standardized effect sizes, facilitating comparisons across different measures. Cohen’s d is defined as the mean difference between groups divided by the pooled standard deviation [34]. Cohen’s statistic ((Mean 1 – Mean 2)/ Pooled SD) can be calculated both when the groups have the same size and when the groups have different sizes (Cohen, 1988. Statistical Power Analysis for the Behavioral Sciences). We also applied linear models were applied to each cognitive domain (global, memory, attention, orientation, verbal fluency, language, and visuospatial skills). Each model used the improvement score as the dependent variable and group (intervention vs. control) as the independent variable.

Covariate Analysis: To explore potential response phenotypes, linear models were used for each covariate of interest (e.g., age, gender, medical history, medication use, family history of dementia, baseline cognitive reserve score, and use of aspirin and statins). The primary outcome was modeled with the covariate, group, and their interaction term to assess whether the intervention effect varied across different covariate groups.

Statistical Testing: All tests were two-sided with a significance level of 5%. Confidence intervals were 95% and two-sided. P-values were reported to three decimal places if ≥0.001; values <0.001 were reported as “<0.001”. Given the exploratory nature of this pilot study, no corrections for multiple comparisons were applied. This approach was chosen to prioritize sensitivity to potential signals that could inform future confirmatory research. Mean and standard deviation were reported to one decimal place more than the original data. Quantiles (median, minimum, maximum) were reported with the same precision as the original data. Estimated parameters not on the same scale as raw observations were reported to significant figures.

Software: Statistical analyses were performed using R version 4.3.0 [35].

Results

Changes in cognitive performance

The average baseline score and (standard deviation) for the global cognitive ability in the control group and in the intervention were 91.3 (±4.9) and 91.3 (±6.2) respectively. The intervention group had a significant improvement from baseline in the global cognitive ability compared to the control group, with an average of 4.6 points from baseline compared to a decrease of 0.5 points in the control group. The non-standardized effect size was 5.14 (95% CI: 3.16 to 7.11) and the standardized effect size was 1.33 (95% CI: 0.77 to 1.90), indicating a statistically significant positive impact of the intervention on global cognitive function When comparing the standardized effect sizes across different domains, memory exhibited the highest effect size, equal to 0.72 (95% CI: 0.19 to 1.25) (Table 2 and Fig 3A and 3B).

Table 2. Effect of MTT 24.5 program on cognitive abilities outcomes.

Outcome	Control Group (N = 20)	Intervention Group (N = 55)	P-value
PRIMARY OUTCOME
Global cognitive ability			<0.001
Score at baseline, mean (±SD)	91.3 (4.9)	91.3 (6.2)
Improvement from baseline, mean	−0.5	4.6
Non-standardized effect size (95% CI) *	–	5.14 (3.16; 7.11)
Standardized effect size (95% CI) **	–	1.33 (0.77; 1.90)
SECONDARY OUTCOMES
Attention cognitive ability			0.055
Score at baseline, mean (±SD)	8.0 (0.0)	7.7 (0.7)
Improvement from baseline, mean	0.0	0.3
Non-standardized effect size (95% CI) *	–	0.27 (−0.001; 0.55)
Standardized effect size (95% CI) **	–	0.51 (−0.02; 1.04)
Memory cognitive ability			0.007
Score at baseline, mean (±SD)	21.2 (3.5)	21.1 (3.9)
Improvement from baseline, mean	0.3	2.4
Non-standardized effect size (95% CI) *	–	2.12 (0.61; 3.63)
Standardized effect size (95% CI) **	–	0.72 (0.19; 1.25)
Verbal fluency cognitive ability			0.018
Score at baseline, mean (±SD)	12.9 (1.3)	12.7 (2.0)
Improvement from baseline, mean	−0.3	0.7
Non-standardized effect size (95% CI)*	–	1.00 (0.19; 1.81)
Standardized effect size (95% CI) **	–	0.63 (0.10; 1.17)
Visuospatial skill’s cognitive ability			0.024
Score at baseline, mean (±SD)	14.2 (1.7)	15.1 (1.2)
Improvement from baseline, mean	−0.2	0.5
Non-standardized effect size (95% CI) *	–	0.73 (0.11; 1.35)
Standardized effect size (95% CI) **	–	0.60 (0.07; 1.13)

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Abbreviations: CI: confidence interval; SD: standard deviation.

*Non-standardized effect size defined as the difference between the mean improvement on the intervention group and the mean improvement on the control group **The standardized effect size defined as the difference between the mean improvement on the intervention group and the mean improvement on the control group, divided by the pooled standard error (Cohen’s d Statistic). Noted that P-values are unadjusted for multiple comparisons due to the exploratory nature of the study.

Fig 3 — The lines represent the 95% confidence interval around each mean, constructed based on the standard error of the mean (SE), the bars depict the mean change score for each group. B. Distribution of the cognitive abilities at pre-and post-intervention.

The impact of the MTT 24.5 program on global cognitive ability across clinical covariates defined by their baseline characteristics and clinical factors was assessed. There was a consistent impact of the intervention across these various subgroups or phenotypes considered. Participants with a baseline ACE score less than 85 showed significantly greater improvement compared to those with a baseline ACE score >85 (p-value: 0.003). (Fig 4).

Fig 4 — Forest plot to show the moderating effects of clinical and demographic covariates are corrected for multiple comparisons when assessing all these moderators.

Discussion

The results of this study demonstrate the effectiveness of the Mental Training Tech 24.5 (MTT24.5) cognitive stimulation program in enhancing cognitive function among healthy adults from the general population. The program significantly improved global cognitive performance and enhanced five of the six cognitive domains evaluated, suggesting its potential as an effective tool for cognitive enhancement.

According to Christopher Hertzog’s theory of cognitive development, cognitive performance has an upper limit, or Cognitive Development Potential (DCP), which is influenced by various factors such as cognitive enrichment, genetics, and health [36].The significant improvements observed in participants following the MTT24.5 program could be a result of its structured approach to learning, which enhances cognitive potential within this framework. By promoting the acquisition of novel, unrelated knowledge, the program stimulates neuroplasticity, improving brain function across different cognitive domains. The role of neuroplasticity in cognitive enhancement is well-established as it is shaped by a combination of biological, environmental, and behavioral factors. MTT24.5 may help optimize cognitive development and mitigate the effects of age-related cognitive decline.

In the context of cognitive function enhancement, the application of Network Control Theory (NCT) [37] offers a useful framework for understanding how stimulating new learning experiences can lead to improved cognitive outcomes. This idea is further elaborated by Bassett and Sporns [38], who posit that brain networks function as complex systems that are governed by controllable states, where certain brain regions serve as hubs that can influence the overall function of the network. This concept aligns with the idea that targeted stimuli, such as new knowledge acquisition and the associated learning techniques, can modulate and strengthen the functional connectivity of these hubs, ultimately improving cognitive outcomes.

When individuals engage in novel learning experiences, such as acquiring new data or knowledge across different domains (e.g., cultural, biological, social sciences), the brain’s neural pathways are challenged and reorganized. This process, driven by cognitive engagement, activates and strengthens brain networks that are essential for functions like memory, attention, and processing speed. The brain’s ability to adapt and reorganize in response to these stimuli is a manifestation of neuroplasticity, which is known to be influenced by learning tasks that involve both novelty and complexity.

For example, incorporating techniques such as Braille literacy, an activity that involves tactile learning and motor coordination, provides a multi-dimensional challenge that engages various brain areas. Braille literacy, as a form of cognitive training, has been shown to enhance sensory integration and motor control, fostering neural connections across multiple brain regions. Through this engagement, the internalization of new knowledge, combined with the specific technique of Braille reading and writing, could facilitate the improvement of cognitive functions like attention, memory, and processing speed.

As outlined in previous studies, such as the Nun Study [16] and the London Taxi Drivers Study [19], lifelong learning and continuous cognitive engagement have been shown to protect cognitive function in aging individuals. These studies provide strong evidence that sustained intellectual stimulation—such as the acquisition of new knowledge and skills—plays a crucial role in building cognitive reserve. By enhancing the brain’s adaptability and functional connectivity, lifelong learning helps preserve cognitive abilities like memory, attention, and processing speed, even in the face of aging.

The MTT24.5 methodology, which is based on explicit learning tasks, stands in contrast to research by J.R. Anderson et al., who demonstrated that identical skills could emerge from both explicit instruction and discovery-based learning [39]. Our findings suggest that future evaluations of MTT24.5 should explore whether the program’s effectiveness is influenced by the mode of learning—whether explicit guidance or more implicit discovery-based strategies lead to the most significant cognitive improvements. This distinction may be particularly important in the application of MTT24.5 to complex skills such as Braille literacy, where different modes of learning may have varying impacts on effectiveness.

Further, the neuroplastic benefits of cognitive training extend beyond traditional cognitive domains. Braille learning, for instance, has been shown to reorganize brain regions associated with sensory and motor functions, even in sighted individuals. Studies on Braille readers have demonstrated reorganization of the visual cortex and other sensory areas, supporting the idea that cognitive stimulation can induce significant neuroplastic changes across sensory systems [40]. This reinforces the potential of MTT24.5 as a tool for inducing broad neuroplastic changes in response to novel learning experiences.

Although most participants had baseline cognitive scores within the normal range, a small subset showed lower baseline scores. It is important to note that MTT24.5 was equally effective across the full spectrum of baseline cognitive performance, suggesting that the program may have universal applicability for cognitive enhancement.

Our results are consistent with the findings of previous studies using online cognitive training platforms such as Lumosity [16]. Both MTT24.5 and Lumosity demonstrate that cognitive training can improve core cognitive abilities, including processing speed, working memory, and fluid reasoning. However, there are critical differences between the two programs. While Lumosity uses games to target specific cognitive skills, MTT24.5 emphasizes the assimilation of new knowledge, with both gamified and non-gamified exercises designed to consolidate this knowledge into long-term memory. In this respect, Lumosity’s focus on skill training is only one component of the broader neuroplastic stimulation aimed at by MTT24.5. Future research is needed to evaluate the relative contributions of the program’s two components to its overall effectiveness. A study comparing data, technology, and a combination of both would provide valuable insights into their individual contributions.

In terms of limitations, the cognitive test battery used in this study could be expanded to mitigate potential bias, as the ACE-R test, like the MMSE and MoCA, is mainly a screening tool for cognitive impairment. However, despite these limitations, the findings indicate that the MTT24.5 program has significant effects across different baseline cognitive scores, with meaningful improvements observed in both lower and higher baseline groups. Additionally, while the study sample was recruited from the general population, the relatively small sample size and the lack of a population-based sampling method may limit the generalizability of the results. Future studies should address these limitations by employing larger, more diverse samples to assess the broader applicability of these findings.

Conclusion

This study provides compelling evidence for the effectiveness of the MTT24.5 cognitive stimulation program in enhancing cognitive function among healthy adults from the general population. The program’s approach—combining the assimilation of novel knowledge with structured learning techniques to stimulate neuroplasticity—resulted in significant improvements across multiple cognitive domains, particularly in memory. Given these promising results, we suggest that future studies explore whether cognitive training should be integrated into recommendations for promoting cognitive health, alongside physical activity, to prevent age-related cognitive decline.

Furthermore, while this study demonstrates significant cognitive improvements, additional research is needed to explore the long-term effects of the program. Specifically, studies should evaluate whether these cognitive improvements persist over time and whether MTT24.5 could delay the onset of age-related cognitive decline, including the risk of dementia. In addition, further investigations comparing different components of the program (data versus technology) will be critical to understanding how each contributes to its effectiveness.

Supporting information

S1 File. Protocol and Statistical Analysis Plan (SAP).

This file includes the original study protocol and the statistical plan that outlines the study objectives, methodology and prespecified statistical methods.

(PDF)

pone.0331193.s001.pdf^{(293.7KB, pdf)}

S2 File. Original Study Protocol (Spanish).

This file contains the original version of the study protocol in Spanish, as approved by the Institutional Review Board (IRB) prior to study initiation.

(PDF)

pone.0331193.s002.pdf^{(346.6KB, pdf)}

S3 File. Data underlying the findings.

This file contains the de-identified dataset used for all analyses presented in the manuscript. The data correspond to the variables and outcomes described in the study protocol and statistical analysis plan.

(XLSX)

pone.0331193.s003.xlsx^{(24.1KB, xlsx)}

S4 File. Code References for lecture of S3 dataset.

(PDF)

pone.0331193.s004.pdf^{(62.8KB, pdf)}

Acknowledgments

We gratefully acknowledge the contributions of K. Ulens (MD, Barcelona) for her collaboration in the database; M. Berrueta, N. Castellana, and L. Gibbons (IECS, Argentina) for their unvaluable contribution for the statistical analysis plan; and Diego García Villanueva for his mentorship.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

References

1.Vollset SE, Murray MJ, Hay TL, Lim CK, Roth KK, Gakidou ATB. Burden of disease scenarios for 204 countries and territories, 2022–2050: A forecasting analysis for the Global Burden of Disease Study 2021. Lancet. 2024;403(10328):2349–76.doi: 10.1016/S0140-6736(24)60921-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Choi M, Sempungu JK, Lee EH, Lee YH. Living longer but in poor health: healthcare system responses to ageing populations in industrialised countries based on the Findings from the Global Burden of Disease Study 2019. BMC Public Health. 2024;24(1):576.doi: 10.1186/s12889-024-18049-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Martinez R, Morsch P, Soliz P, Hommes C, Ordunez P, Vega E. Life expectancy, healthy life expectancy, and burden of disease in older people in the Americas, 1990-2019: a population-based study. Rev Panam Salud Publica. 2021;45:e114.doi: 10.26633/RPSP.2021.114 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Buchanan KL, Grindstaff JL, Pravosudov VV. Condition dependence, developmental plasticity, and cognition: implications for ecology and evolution. Trends Ecol Evol. 2013;28(5):290–6.doi: 10.1016/j.tree.2013.02.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Guez A, Peyre H, Williams C, Labouret G, Ramus F. The epidemiology of cognitive development. Cognition. 2021;213:104690.doi: 10.1016/j.cognition.2021.104690 [DOI] [PubMed] [Google Scholar]
6.Lövdén M, Fratiglioni L, Glymour MM, Lindenberger U, Tucker-Drob EM. Education and Cognitive Functioning Across the Life Span. Psychol Sci Public Interest. 2020;21(1):6–41.doi: 10.1177/1529100620920576 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Smith J, Jones A, Brown C. The Role of Cognitive Training in Promoting Brain Health: A Call for Integration into Adult Life. Journal of Neurology and Neurological Disorders. 2023;10(2):115–25. [Google Scholar]
8.Lindenberger U. Human cognitive aging: corriger la fortune?. Science. 2014;346(6209):572–8.doi: 10.1126/science.1254403 [DOI] [PubMed] [Google Scholar]
9.May A. Experience-dependent structural plasticity in the adult human brain. Trends Cogn Sci. 2011;15(10):475–82.doi: 10.1016/j.tics.2011.08.002 [DOI] [PubMed] [Google Scholar]
10.Mora F, Segovia G, del Arco A. Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain Res Rev. 2007;55(1):78–88.doi: 10.1016/j.brainresrev.2007.03.011 [DOI] [PubMed] [Google Scholar]
11.Scarmeas N, Stern Y. Cognitive reserve and lifestyle. J Clin Exp Neuropsychol. 2003;25(5):625–33.doi: 10.1076/jcen.25.5.625.14576 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Boyke J, Driemeyer J, Gaser C, Büchel C, May A. Training-induced brain structure changes in the elderly. J Neurosci. 2008;28(28):7031–5.doi: 10.1523/JNEUROSCI.0742-08.2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Su F, Xu W. Enhancing Brain Plasticity to Promote Stroke Recovery. Front Neurol. 2020;11:554089.doi: 10.3389/fneur.2020.554089 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Gómez-Soria I, Iguacel I, Aguilar-Latorre A, Peralta-Marrupe P, Latorre E, Zaldívar JNC, et al. Cognitive stimulation and cognitive results in older adults: A systematic review and meta-analysis. Arch Gerontol Geriatr. 2023;104:104807.doi: 10.1016/j.archger.2022.104807 [DOI] [PubMed] [Google Scholar]
15.Justo-Henriques SI, Pérez-Sáez E, Marques-Castro AE, Carvalho JO. Effectiveness of a year-long individual cognitive stimulation program in Portuguese older adults with cognitive impairment. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2023;30(3):321–35.doi: 10.1080/13825585.2021.2023458 [DOI] [PubMed] [Google Scholar]
16.Hardy JL, Nelson RA, Thomason ME, Sternberg DA, Katovich K, Farzin F, et al. Enhancing Cognitive Abilities with Comprehensive Training: A Large, Online, Randomized, Active-Controlled Trial. PLoS One. 2015;10(9):e0134467.doi: 10.1371/journal.pone.0134467 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Snowdon DA. Healthy aging and dementia: findings from the Nun Study. Ann Intern Med. 2003;139(5 Pt 2):450–4. [DOI] [PubMed] [Google Scholar]
18.Iacono D, Markesbery WR, Gross M, Pletnikova O, Rudow G, Zandi P, et al. The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life. Neurology. 2009;73(9):665–73.doi: 10.1212/WNL.0b013e3181b01077 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Nelson ME, Jester DJ, Petkus AJ, Andel R. Cognitive Reserve, Alzheimer’s Neuropathology, and Risk of Dementia: A Systematic Review and Meta-Analysis. Neuropsychol Rev. 2021;31(2):233–50.doi: 10.1007/s11065-021-09478-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Maguire EA, Woollett K, Spiers HJ. London taxi drivers and bus drivers: a structural MRI and neuropsychological analysis. Hippocampus. 2006;16(12):1091–101.doi: 10.1002/hipo.20233 [DOI] [PubMed] [Google Scholar]
21.Griesbauer E-M, Manley E, Wiener JM, Spiers HJ. London taxi drivers: A review of neurocognitive studies and an exploration of how they build their cognitive map of London. Hippocampus. 2022;32(1):3–20.doi: 10.1002/hipo.23395 [DOI] [PubMed] [Google Scholar]
22.Boot WR, Kramer AF. The brain-games conundrum: does cognitive training really sharpen the mind?. Cerebrum. 2014;2014:15. [PMC free article] [PubMed] [Google Scholar]
23.Owen AM, Hampshire A, Grahn JA, Stenton R, Dajani S, Burns AS, et al. Putting brain training to the test. Nature. 2010;465(7299):775–8.doi: 10.1038/nature09042 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Gobet F, Sala G. Cognitive Training: A Field in Search of a Phenomenon. Perspect Psychol Sci. 2023;18(1):125–41.doi: 10.1177/17456916221091830 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Au J, Gibson BC, Bunarjo K, Buschkuehl M, Jaeggi SM. Quantifying the Difference between Active and Passive Control Groups in Cognitive Interventions Using two Meta-Analytical Approaches. J Cogn Enhanc. 2020;4(2):192–210.doi: 10.1007/s41465-020-00164-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Matuszewski J, Kossowski B, Bola Ł, Banaszkiewicz A, Paplińska M, Gyger L, et al. Brain plasticity dynamics during tactile Braille learning in sighted subjects: Multi-contrast MRI approach. Neuroimage. 2021;227:117613.doi: 10.1016/j.neuroimage.2020.117613 [DOI] [PubMed] [Google Scholar]
27.Bola Ł, Siuda-Krzywicka K, Paplińska M, Sumera E, Hańczur P, Szwed M. Braille in the Sighted: Teaching Tactile Reading to Sighted Adults. PLoS One. 2016;11(5):e0155394.doi: 10.1371/journal.pone.0155394 [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Philip BA, Frey SH. Increased functional connectivity between cortical hand areas and praxis network associated with training-related improvements in non-dominant hand precision drawing. Neuropsychologia. 2016;87:157–68.doi: 10.1016/j.neuropsychologia.2016.05.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.NCD Countdown 2030 collaborators. NCD Countdown 2030: worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4. Lancet. 2018;392(10152):1072–88.doi: 10.1016/S0140-6736(18)31992-5 [DOI] [PubMed] [Google Scholar]
30.Santos Lopes da Silva L, Tasinafo Júnior MF, da Silva Gonçalves L, Polveiro da Silva A, Pengo Almeida Leite LF, Scatena Fávero L, et al. Does Multicomponent Training Improve Cognitive Function in Older Adults Without Cognitive Impairment? A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Med Dir Assoc. 2023;24(6):765–72.doi: 10.1016/j.jamda.2023.03.004 [DOI] [PubMed] [Google Scholar]
31.Rebok GW, Ball K, Guey LT, Jones RN, Kim H-Y, King JW, et al. Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. J Am Geriatr Soc. 2014;62(1):16–24. doi: 10.1111/jgs.12607 [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Torralva T, Roca M, Gleichgerrcht E, Bonifacio A, Raimondi C, Manes F. Validation of the Spanish Version of the Addenbrooke’s Cognitive Examination-Revised (ACE-R). Neurologia. 2011;26(6):351–6.doi: 10.1016/j.nrl.2010.10.013 [DOI] [PubMed] [Google Scholar]
33.Leoón, Garcića-Garcića J, Roldaán-Tapia L. Cognitive Reserve Scale and ageing. Anales de psicología. 2016;32(1):218–23. [Google Scholar]
34.Goulet-Pelletier J-C, Cousineau D. A review of effect sizes and their confidence intervals, Part I: The Cohen’s d family. TQMP. 2018;14(4):242–65.doi: 10.20982/tqmp.14.4.p242 [DOI] [Google Scholar]
35.R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. 2023. [Google Scholar]
36.Hertzog C, Kramer AF, Wilson RS, Lindenberger U. Enrichment Effects on Adult Cognitive Development: Can the Functional Capacity of Older Adults Be Preserved and Enhanced? Psychol Sci Public Interest. 2008;9(1):1–65. [DOI] [PubMed] [Google Scholar]
37.Sporns O, Chialvo DR, Kaiser M, Hilgetag CC. Organization, development and function of complex brain networks. Trends Cogn Sci. 2004;8(9):418–25.doi: 10.1016/j.tics.2004.07.008 [DOI] [PubMed] [Google Scholar]
38.Bassett DS, Sporns O. Network neuroscience. Nat Neurosci. 2017;20(3):353–64.doi: 10.1038/nn.4502 [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Anderson JR, Betts S, Bothell D, Lebiere C. Discovering skill. Cogn Psychol. 2021;129:101410.doi: 10.1016/j.cogpsych.2021.101410 [DOI] [PubMed] [Google Scholar]
40.Siuda-Krzywicka K, Bola Ł, Paplińska M, Sumera E, Jednoróg K, Marchewka A, et al. Massive cortical reorganization in sighted Braille readers. Elife. 2016;5:e10762.doi: 10.7554/eLife.10762 [DOI] [PMC free article] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0331193.r001

Decision Letter 0

Roya Khanmohammadi

4 Mar 2025

Dear Dr. Kotliar,

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: The authors have presented a highly relevant cognitive stimulation program (MTT24.5) aimed to improve global cognitive performance in healthy, older adults. While this paper is overall well written, there are theoretical and methodological concerns, which lead me to my recommendation of “revise and resubmit”.

Introduction:

Throughout the entire introduction, the authors include statements, commentary, and previous studies without citations. Given that the reference list includes more citations than what was used in this section, perhaps some were left out.

The introduction provides vague information on previous studies that have shown evidence for the benefits of engaging in multiple-skill learning interventions to enhance neuroplasticity, and improve cognitive reserve in healthy adults. While much of the introduction states that learning interventions improve cognitive skills, there is a lack of literature that addresses the key objective in this study: testing a program where learning multiple skills can enhance multiple brain regions. Rather than broadly discussing how learning interventions improve ‘neuroplasticity’ and ‘cognitive function’, address how these interventions have improved the cognitive functions measured in this study, such as memory, attention, verbal fluency, language, and visuospatial skills. Providing this extra clarity can strengthen the introduction.

Although the importance of investigating the gap in evidence on the effectiveness of cognitive training interventions in healthy older adults is addressed, there is a lack of literature focused on the authors’ choice of subjects: healthy individuals, rather than individuals with cognitive impairments. A stronger focus on studies involving healthy older adults would better support the study’s rationale and help formulate a more specific hypothesis.

The authors state that this pilot study aims to develop a hypothesis to validate the effectiveness of the MTT24.5 for improving cognitive performance, however this approach may hinder the validity of this technique as a more precise hypothesis could have been formulated based on the previous success of cognitive learning interventions with similar approaches in healthy older adults.

Method:

While the pairs (DATA and TECHS) are introduced and methodologically explained thoroughly, it remains theoretically unclear why the authors chose these pairs and how they both contributed to the study’s objective.

A few minor methodological details are missing in this design. For example, how were these pairs administered, executed, and monitored? Were the pairs performed digitally or in a classroom setting? It is stated that this is an in-person study, however there is a lack of information regarding the study’s procedures.

Results:

The results section of the paper includes the demographic information of the participants. However, this table would be more appropriate if presented in the Method section.

Reviewer #2: Introduction

Providing a deeper explanation of how MTT24.5 promotes neuroplasticity would enhance the manuscript. Discussing theoretical frameworks, such as network control theory, could offer valuable insights into the underlying mechanisms.

The last sentence of the introduction states that "This cohort represents the general population." Is this study a clinical trial or a cohort study?

Method

Why is the ratio of the intervention group to the control group considered to be 2:1?

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2025 Oct 1;20(10):e0331193. doi: 10.1371/journal.pone.0331193.r002

Author response to Decision Letter 1

11 Apr 2025

Dear Reviewers, #1 and #2,

We would like to sincerely thank you for the time and effort you have dedicated to reviewing our manuscript. We deeply appreciate your thoughtful comments and feedback. We are very hopeful to communicate our findings to our colleagues through the prestigious scientific journal, PLOS ONE.

Below, we respond to each of the suggestions, comments, and recommendations from the reviewers. We also confirm that we have made the necessary changes and additions to meet all the requirements outlined in your evaluation letter.

We believe these changes address all the concerns raised and have significantly improved the manuscript. We are grateful for your guidance throughout this process and look forward to your feedback.

Thank you once again for your time and support.

Sincerely,

Carol Kotliar, PhD

Responses to Reviewer #1

1. Comment: “Throughout the entire introduction, the authors include statements, commentary, and previous studies without citations. Given that the reference list includes more citations than what was used in this section, perhaps some were left out.”

Response: Following your observation, we have included the appropriate citations for all statements, commentary, and previous studies as requested. The reference list has been reviewed and updated to complement this valuable observation. (#See pages 3 to 5 for the updated introduction with the corresponding citations from references 1 to 28, which can be found in the references section on pages 24 to 27)

2. Comment: “Rather than broadly discussing how learning interventions improve ‘neuroplasticity’ and ‘cognitive function,’ address how these interventions have improved the cognitive functions measured in this study, such as memory, attention, verbal fluency, language, and visuospatial skills. Providing this extra clarity can strengthen the introduction.”

Response: We consider your comment extremely valuable in strengthening the focus of the introduction on our study's specific scope. We have restructured and enhanced the introduction, providing a foundation with the corresponding citations that address how learning interventions have improved the specific functions measured in this study. (#See the modifications on pages 3 to 5 throughout the entire revised introduction)

3. Comment: “A stronger focus on studies involving healthy older adults would better support the study’s rationale and help formulate a more specific hypothesis. The authors state that this pilot study aims to develop a hypothesis to validate the effectiveness of the MTT24.5 for improving cognitive performance, however, this approach may hinder the validity of this technique as a more precise hypothesis could have been formulated based on the previous success of cognitive learning interventions with similar approaches in healthy older adults.”

Response: We also appreciate this valuable comment. We have now focused more on studies involving healthy adults in the introduction and emphasized this condition among of the adults included in the study in the formulation of the hypothesis. Additionally, we thank the reviewer for highlighting this specific characteristic of our population, which could undoubtedly be considered for future prevention studies to be applied in the general population. Given the increased life expectancy, brain stimulation or training could be a potential recommendation to contribute to the reduction of future cognitive decline risk. (See the modifications on pages 3 to 5 throughout the entire revised introduction)

4. Comment: “While the pairs (DATA and TECHS) are introduced and methodologically explained thoroughly, it remains theoretically unclear why the authors chose these pairs and how they both contributed to the study’s objective.”

Response: Thank you for your valuable question. The origin of the MTT design, utilizing binomial units of "DATA" and "TECHS," was proposed by the lead author of the manuscript, Carol Kotliar, PhD, who also registered it as an intellectual property. The core idea was to create a structured, progressive learning system that would introduce new knowledge over time. The term "DATA" was chosen to describe these new units of knowledge, each represented as a simple statement encapsulated in a concise sentence. The original concept was to design the knowledge in such a way that each "DATA" unit could stand independently without requiring interconnection with others. To achieve this, the knowledge was carefully selected from four main scientific fields: cultural, formal (including logic and mathematics), biological, and social sciences. This diversified approach aimed to stimulate various areas of the brain, with some of the knowledge deliberately positioned outside the participant's usual domain of expertise. Given that it is unlikely an individual would have a professional or personal interest in all these areas, this strategy ensured broader cognitive engagement, pushing participants beyond their comfort zones and established knowledge base.

Data for each unit was carefully sourced using search engines focusing on these four fields. Each "DATA" point was distilled into a single, easily memorable sentence. To enhance the engagement and accessibility of the material, additional resources such as videos, images, anecdotes, and emotional cues were incorporated alongside the core content.

In parallel, the term "TECHS" was coined to describe the methodologies used to facilitate the learning of the "DATA." These techniques were selected based on their documented association with neuroplastic changes in the brain, as evidenced by structural and functional studies in the scientific literature. Among the various techniques explored, Braille literacy was identified as particularly effective, with approximately 60% of the "TECHS" incorporating Braille reading and writing exercises. This inclusion was grounded in the evidence of its neuroplastic benefits, stimulating brain regions associated with sensory integration, motor control, and memory retention.

Participants in the MTT program developed Braille reading and writing skills as part of the curriculum, as well as the ability to perform mirrored writing with both hands simultaneously. The content written and read always corresponded to the new "DATA," reinforcing the memorization process throughout the activities.

The dual structure of the MTT program comprising "DATA" (the new knowledge) and "TECHS" (the methods for learning) was designed to promote dynamic cognitive engagement. By offering a varied and structured approach, it aimed to enhance neuroplasticity through the stimulation of multiple brain regions and encourage the development of novel cognitive pathways in healthy adults. (A summarized expansion of this justification for the Data-Tech pair has been included in the Methods section on pages 11 and 12)

5. Comment: “A few minor methodological details are missing in this design. For example, how were these pairs administered, executed, and monitored? Were the pairs performed digitally or in a classroom setting?”

Response: The binomial Data-Tech pair is presented in a classroom setting. The sessions are taught in person by a certified trainer who uses standardized materials, including videos, images, oral descriptions, and various resources such as sheets of paper, pencils, Braille tablets with punchers, a luminous button, a semi-baked ball for foot pressure, a calculator, Wisconsin cards, the Stroop Color Test, and other tools integrated into the techniques. Each participant is assigned specific materials. There is one trainer for every 20 participants, with an assistant; the number of assistants increases as the class size grows. To complete the full MTT, participants must attend 12 consecutive sessions.

The program is executed sequentially, with all data sets organized for each class. Each session combines one piece of knowledge from each of the four scientific fields cultural, social, formal, and biological sciences; administered in a specific order across the 12 sessions, along with their corresponding techniques. The trainer explains each piece of data to all participants during each session, followed by the techniques associated with that data. After completing the first data-tech pair, the process progresses to the second, then the third, continuing in this structured manner throughout each session.

A participant is considered to have completed the program if they attend at least 80% of the sessions. If a participant is unable to attend a session, they are encouraged to make it up in a later class, but they cannot miss any classes without attending a make-up session. (#Following your recommendation, the description is expanded in the Methods section on page 10.)"

III. Responses to reviewer #2

1. Comment: “Providing a deeper explanation of how MTT24.5 promotes neuroplasticity would enhance the manuscript. Discussing theoretical frameworks, such as network control theory, could offer valuable insights into the underlying mechanisms.”

Response: To address the reviewer’s request, we provided a deeper explanation of how the Mental Training Tech 24.5 (MTT24.5) program may promote neuroplasticity by integrating the theoretical framework of Network Control Theory (NCT). This analysis will link the effects of the program on cognitive functions (attention, memory, verbal fluency, visuospatial skills, and processing speed) to the principles of NCT. We appreciate this valuable suggestion, which has been incorporated into the manuscript. Considering that this perspective adds depth to the interpretation of the results, we believe that its inclusion in the discussion strongly enhances the impact of these concepts.

We believe this significantly enriches our manuscript. (#See the pages 17 and 18)

2. Comment: “The last sentence of the introduction states that 'This cohort represents the general population.' Is this study a clinical trial or a cohort study?”

Response: This was certainly necessary to modify. We have updated the last sentence of the introduction, clarifying that the study is a clinical trial, not a cohort study. (#See the correction in introduction section at page 5)

Section: Method

3. Comment: “Why is the ratio of the intervention group to the control group considered to be 2:1?”

Response: A 2:1 randomization ratio was chosen to facilitate recruitment among healthy volunteers, offering a higher chance of receiving the Intervention. In the case of potentially improving cognitive function, this ratio, which allocates more 'healthy' participants to the experimental treatment in a short period, can promote better adherence and recruitment. This approach was particularly relevant given that this was a pilot study. By using this design, a larger sample size in the intervention group was achieved. The decision was made after careful consideration of study resources and ethical guidelines to ensure a fair and scientifically sound comparison between groups.

Section: Results

4. Comment (d) of Reviewer #2: “The results section of the paper includes the demographic information of the participants. However, this table would be more appropriate if presented in the Methods section.”

Response: The table describing the demographic information of the participants has been moved to the Methods section as suggested. (#see page 9)

Attachment

Submitted filename: RESPONSE TO REVIEWERS .pdf

pone.0331193.s006.pdf^{(228.7KB, pdf)}

PLoS One. doi: 10.1371/journal.pone.0331193.r003

Decision Letter 1

Roya Khanmohammadi

22 Apr 2025

Dear Dr. Kotliar,

While prior concerns have been largely addressed, a few minor revisions are still needed:

Introduction : Please reference platforms like Lumosity earlier, as this supports the novelty of your work.
Methods : Clarify and streamline the explanation of the DATA and TECHS components to improve readability and reduce redundancy.

We look forward to receiving your revised manuscript.

Please submit your revised manuscript by Jun 06 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Roya Khanmohammadi, Ph.D

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: The author’s have presented a highly relevant cognitive stimulation program (MTT24.5), displaying improved cognitive abilities in healthy adults. Many of the previous concerns of the manuscript were resolved, however there are a few minor theoretical concerns, which lead me to my recommendation of “revise and resubmit”.

Introduction:

At the end of the discussion, the authors mention that their findings are consistent with online cognitive training platforms such as Lumosity. However, this is the first time the authors mention this online cognitive training platform, only at the end of the paper. Considering both Luminosity and the current study highlight similar benefits of enhanced cognitive abilities, it would strengthen the introduction and display novelty to the current study if Lumosity were introduced before the current study.

Methods:

The authors provided information on how the DATA and TECHS components are used for the intervention; however, the overall organization of these concepts throughout the methods section is not optimal. Especially when initially introducing the components, they are abstract and contain numerous redundancies. As these two components are central to the intervention, it is crucial that they are explained more clearly.

Reviewer #2: I appreciate the authors’ efforts — the comments have been thoughtfully addressed and implemented effectively.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #1: No

Reviewer #2: No

**********

PLoS One. 2025 Oct 1;20(10):e0331193. doi: 10.1371/journal.pone.0331193.r004

Author response to Decision Letter 2

20 May 2025

The minor changes requested by Reviewer #1 were implemented, including the mention of the study on the cognitive platform Lumosity in the Introduction, and a rewritten description of the intervention in the Methods section to enhance clarity. Due to the inclusion of the Hardy et al. study in the Introduction, its position in the reference list was updated, which required adjusting the overall numbering of references accordingly.

Attachment

Submitted filename: RESPONSE TO REVIEWERS (2).docx

pone.0331193.s007.docx^{(21.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0331193.r005

Decision Letter 2

Roya Khanmohammadi

28 May 2025

Dear Dr. Kotliar,

We sincerely appreciate the substantial improvements you have made and the way you have addressed the previous reviewer comments.

Most of the concerns raised in the earlier round of review have been satisfactorily resolved. However, Reviewer 1 has now provided a few remaining theoretical concerns that require your attention before the manuscript can proceed further.

Please consider the following points raised by Reviewer 1:

Introduction:

At the end of the discussion, you mention that your findings are consistent with online cognitive training platforms such as Lumosity. However, this is the first instance where Lumosity is mentioned in the manuscript. Since both your intervention and Lumosity report similar cognitive benefits, it is recommended that you introduce Lumosity earlier in the Introduction , to better highlight the novelty and relevance of your study.
Methods:

While you have described how the DATA and TECHS components are used in the intervention, their initial presentation remains somewhat abstract and contains redundancies. Given that these components are central to your cognitive training program, we encourage you to revise this section for improved clarity and organization. A clearer and more concise explanation will strengthen the reader’s understanding of your intervention model.

We kindly ask that you revise the manuscript in accordance with these comments and submit a revised version for further consideration.

Thank you once again for your efforts and your contribution to the field.

Please submit your revised manuscript by Jul 12 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Roya Khanmohammadi, Ph.D

Academic Editor

PLOS ONE

Journal Requirements:

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

The author’s have presented a highly relevant cognitive stimulation program (MTT24.5), displaying improved cognitive abilities in healthy adults. Many of the previous concerns of the manuscript were resolved, however there are a few minor theoretical concerns, which lead me to my recommendation of “revise and resubmit”.

Introduction:

Methods:

PLoS One. 2025 Oct 1;20(10):e0331193. doi: 10.1371/journal.pone.0331193.r006

Author response to Decision Letter 3

3 Jul 2025

May 18, 2025.

Response letter to Academic Editor and to Reviewers

PONE-D-24-57989: A New Program for Systematically Enhancing Cognitive Reserve in Healthy Adults: A Pilot Randomized Active-Controlled Study

Dear Dr. Khanmohammadi, Ph.D, Academic Editor

Dear Reviewers, #1 and #2

We would like to express our sincere gratitude for the time and effort you have dedicated to reviewing our manuscript. We greatly appreciate your thoughtful feedback. In response to your comments, we have made the necessary revisions to the manuscript, as detailed below.

The two changes requested by Reviewer #1 were implemented, including the mention of the study on the cognitive platform Lumosity in the Introduction, and a rewritten description of the intervention in the Methods section to enhance clarity. Due to the inclusion of the Hardy et al. study in the Introduction, its position in the reference list was updated, which required adjusting the overall numbering of references accordingly.

These revisions address the points raised and we believe they have further strengthened the manuscript. We are hopeful that this second revised version meets your expectations and look forward to your feedback.

Thank you once again for your valuable support.

Sincerely,

Carol Kotliar, PhD

Responses to Reviewer #1

1. Comment (Introduction): “At the end of the discussion, the authors mention that their findings are consistent with online cognitive training platforms such as Lumosity. However, this is the first time the authors mention this online cognitive training platform, only at the end of the paper. Considering both Luminosity and the current study highlight similar benefits of enhanced cognitive abilities, it would strengthen the introduction and display novelty to the current study if Lumosity were introduced before the current study.”

Response: Thank you for your valuable observation regarding the mention of Lumosity. We agree that introducing this online cognitive training platform earlier in the manuscript improves the context and helps emphasize the novelty of our study. Following your recommendation, we have now included a mention of Lumosity in the Introduction section (page 3, lines 63 to 69).

2. Comment (Methods):” The authors provided information on how the DATA and TECHS components are used for the intervention; however, the overall organization of these concepts throughout the methods section is not optimal. Especially when initially introducing the components, they are abstract and contain numerous redundancies. As these two components are central to the intervention, it is crucial that they are explained more clearly.”

Response: We appreciate your comment regarding the organization and clarity of the DATA and TECHS components in the Methods section. We understand the importance of providing a clear and concise explanation, especially as these two components are central to the intervention. In response to your requirement, we have revised the description to improve clarity, eliminating abstract terms and redundant sentences. We have carefully reviewed the revised text to ensure its clarity and coherence. Please refer to pages 9 to 11 for the updated description.

Attachment

Submitted filename: RESPONSE_TO_REVIEWERS_(2)_auresp_3.docx

pone.0331193.s008.docx^{(21.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0331193.r007

Decision Letter 3

Roya Khanmohammadi

27 Jul 2025

Dear Dr. Kotliar,

The statistical reviewer found your study to be reasonably well-designed, with appropriate data analysis. However, several minor but important issues were raised that require your attention before further consideration:

Sample size justification – Please clarify the rationale for using an effect size of 0.80. Was this based on prior literature, previous data, or another source?
Multiple comparisons – Table 2 includes several secondary cognitive outcomes. Please indicate whether any corrections for multiple comparisons were applied, particularly for measures such as attention, verbal fluency, and visuospatial skills. Even in a pilot study, this should be addressed.
Randomization ratio – While the 2:1 randomization appears justifiable, kindly explain the rationale for this choice explicitly in the manuscript to inform the reader.

Please submit your revised manuscript by Sep 10 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Roya Khanmohammadi, Ph.D

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #3: Yes

**********

Reviewer #3: The study is reasonably designed and the data analysis appropriate. However, there are several minor issues that should be considered.

1. One needs the rationale for the ES =0.80 in the sample size justification. Is it from past data, the literature or otherwise. Please explain.

2. There is no mention of multiple comparisons in the text or supplement protocol information. Table 2 has several secondary endpoints reported. Any adjustment of the p-values for multiple comparisons especially for Attention cognitive ability, Verbal fluency cognitive ability and Visuospatial skills cognitive ability. Even in a pilot setting this should be considered.

3. The need for the 2:1 randomization seems intuitively reasonable, but please explain the rationale for such for the reader.

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #3: No

**********

PLoS One. 2025 Oct 1;20(10):e0331193. doi: 10.1371/journal.pone.0331193.r008

Author response to Decision Letter 4

5 Aug 2025

Dear Reviewer, #3

In response to your comments, we have made the necessary revisions to the manuscript, as detailed below.

The 3 minor revisions requested were implemented, including their detailed description for the readers inside the manuscript.

These revisions address the points raised and we believe they have further strengthened the manuscript. We are hopeful that this third revised version meets your expectations and look forward to the final acceptance of the manuscript.

Thank you once again for your valuable support.

Sincerely,

Carol Kotliar, PhD

Responses to Reviewer #3

1. Comment: “Sample size justification – Please clarify the rationale for using an effect size of 0.80. Was this based on prior literature, previous data, or another source?

Response: The effect size of 0.80 used in our sample size calculation was based on prior literature, particularly the methodology and effect size interpretation used in the ACTIVE trial (Advanced Cognitive Training for Independent and Vital Elderly).

Although the observed effects in ACTIVE ranged from small to moderate (e.g., 0.23 for reasoning and 0.66 for speed), we considered an effect size of 0.80 as a conservative target to detect a meaningful difference with sufficient power, assuming a best-case scenario for the intervention's impact.

Additionally, we considered the characteristics of our primary cognitive outcome measure. For example, in the Addenbrooke’s Cognitive Examination (ACE), a 1-point difference is clinically relevant for identifying cognitive decline. Therefore, assuming an intervention could achieve at least a moderate to large improvement (corresponding to 4 points, SD = 5.4, d = 0.8) was both clinically reasonable and consistent with previous literature on cognitive training effects.

We introduced this explanation also in the manuscript in the corresponding section to inform the reader. (Page 13)

2. Comment: “Multiple comparisons” Table 2 includes several secondary cognitive outcomes. Please indicate whether any corrections for multiple comparisons were applied, particularly for measures such as attention, verbal fluency, and visuospatial skills. Even in a pilot study, this should be addressed.

Response: Thank you for this important comment. We fully agree that the issue of multiple comparisons should be addressed, even in a pilot study. Given the exploratory nature of this pilot study, no corrections for multiple comparisons were applied. This decision was made to maximize sensitivity to potential signals that could inform future confirmatory studies. In pilot or exploratory studies like this one, it’s common not to apply these corrections. In these kinds of studies, the focus is more on detecting potential signals of an effect, even if that means accepting a higher risk of false positives.

Following your suggestion, we addressed it with a clearly state of this approach in the methods section as follows:

Changes in the manuscript:

A) We have added the following sentence to the Statistical Analysis section (at page 13):

"Given the exploratory nature of this pilot study, no correction for multiple comparisons was applied to secondary cognitive outcomes. This decision was based on the aim of generating hypotheses rather than confirming definitive effects. We acknowledge that this approach increases the risk of type I error, and therefore, the findings should be interpreted with caution and considered hypothesis-generating.”

B) We have also added a corresponding footnote in the manuscript at Table 2 (PAGE 14)

"P-values are unadjusted for multiple comparisons due to the exploratory nature of the study."

3. Comment: “Randomization ratio – While the 2:1 randomization appears justifiable, kindly explain the rationale for this choice explicitly in the manuscript to inform the reader.”

Response: A 2:1 randomization ratio was choice to support recruitment and enhance adherence among healthy volunteers by increasing the likelihood of being assigned to the intervention group. In studies involving cognitive enhancement in healthy populations, such an approach can be particularly effective in motivating participation. Given the nature of this pilot study, a larger sample size in the intervention arm allowed for a more informative preliminary assessment of feasibility and potential effects. This decision was made after careful consideration of ethical principles, study objectives, and available resources, ensuring a scientifically valid comparison between groups.

# See at manuscript PAGE 6: We incorporated the explanation as you requested into the manuscript to inform the reader.

Best regards,

Carol Kotliar, PhD.

Attachment

Submitted filename: Response to Reviewer #3.docx

pone.0331193.s009.docx^{(23.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0331193.r009

Decision Letter 4

Roya Khanmohammadi

13 Aug 2025

A New Program for Systematically Enhancing Cognitive Reserve in Healthy Adults: A Pilot Randomized Active-Controlled Trial

PONE-D-24-57989R4

Dear Dr. Kotliar,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Roya Khanmohammadi, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #3: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #3: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #3: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #3: (No Response)

**********

Reviewer #3: (No Response)

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #3: No

**********

PLoS One. doi: 10.1371/journal.pone.0331193.r010

Acceptance letter

Roya Khanmohammadi

PONE-D-24-57989R4

PLOS ONE

Dear Dr. Kotliar,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

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on behalf of

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Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 File. Protocol and Statistical Analysis Plan (SAP).

This file includes the original study protocol and the statistical plan that outlines the study objectives, methodology and prespecified statistical methods.

(PDF)

pone.0331193.s001.pdf^{(293.7KB, pdf)}

S2 File. Original Study Protocol (Spanish).

This file contains the original version of the study protocol in Spanish, as approved by the Institutional Review Board (IRB) prior to study initiation.

(PDF)

pone.0331193.s002.pdf^{(346.6KB, pdf)}

S3 File. Data underlying the findings.

(XLSX)

pone.0331193.s003.xlsx^{(24.1KB, xlsx)}

S4 File. Code References for lecture of S3 dataset.

(PDF)

pone.0331193.s004.pdf^{(62.8KB, pdf)}

Attachment

Submitted filename: RESPONSE TO REVIEWERS .pdf

pone.0331193.s006.pdf^{(228.7KB, pdf)}

Attachment

Submitted filename: RESPONSE TO REVIEWERS (2).docx

pone.0331193.s007.docx^{(21.7KB, docx)}

Attachment

Submitted filename: RESPONSE_TO_REVIEWERS_(2)_auresp_3.docx

pone.0331193.s008.docx^{(21.7KB, docx)}

Attachment

Submitted filename: Response to Reviewer #3.docx

pone.0331193.s009.docx^{(23.4KB, docx)}

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

[pone.0331193.ref001] 1.Vollset SE, Murray MJ, Hay TL, Lim CK, Roth KK, Gakidou ATB. Burden of disease scenarios for 204 countries and territories, 2022–2050: A forecasting analysis for the Global Burden of Disease Study 2021. Lancet. 2024;403(10328):2349–76.doi: 10.1016/S0140-6736(24)60921-3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref002] 2.Choi M, Sempungu JK, Lee EH, Lee YH. Living longer but in poor health: healthcare system responses to ageing populations in industrialised countries based on the Findings from the Global Burden of Disease Study 2019. BMC Public Health. 2024;24(1):576.doi: 10.1186/s12889-024-18049-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref003] 3.Martinez R, Morsch P, Soliz P, Hommes C, Ordunez P, Vega E. Life expectancy, healthy life expectancy, and burden of disease in older people in the Americas, 1990-2019: a population-based study. Rev Panam Salud Publica. 2021;45:e114.doi: 10.26633/RPSP.2021.114 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref004] 4.Buchanan KL, Grindstaff JL, Pravosudov VV. Condition dependence, developmental plasticity, and cognition: implications for ecology and evolution. Trends Ecol Evol. 2013;28(5):290–6.doi: 10.1016/j.tree.2013.02.004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref005] 5.Guez A, Peyre H, Williams C, Labouret G, Ramus F. The epidemiology of cognitive development. Cognition. 2021;213:104690.doi: 10.1016/j.cognition.2021.104690 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref006] 6.Lövdén M, Fratiglioni L, Glymour MM, Lindenberger U, Tucker-Drob EM. Education and Cognitive Functioning Across the Life Span. Psychol Sci Public Interest. 2020;21(1):6–41.doi: 10.1177/1529100620920576 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref007] 7.Smith J, Jones A, Brown C. The Role of Cognitive Training in Promoting Brain Health: A Call for Integration into Adult Life. Journal of Neurology and Neurological Disorders. 2023;10(2):115–25. [Google Scholar]

[pone.0331193.ref008] 8.Lindenberger U. Human cognitive aging: corriger la fortune?. Science. 2014;346(6209):572–8.doi: 10.1126/science.1254403 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref009] 9.May A. Experience-dependent structural plasticity in the adult human brain. Trends Cogn Sci. 2011;15(10):475–82.doi: 10.1016/j.tics.2011.08.002 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref010] 10.Mora F, Segovia G, del Arco A. Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain Res Rev. 2007;55(1):78–88.doi: 10.1016/j.brainresrev.2007.03.011 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref011] 11.Scarmeas N, Stern Y. Cognitive reserve and lifestyle. J Clin Exp Neuropsychol. 2003;25(5):625–33.doi: 10.1076/jcen.25.5.625.14576 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref012] 12.Boyke J, Driemeyer J, Gaser C, Büchel C, May A. Training-induced brain structure changes in the elderly. J Neurosci. 2008;28(28):7031–5.doi: 10.1523/JNEUROSCI.0742-08.2008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref013] 13.Su F, Xu W. Enhancing Brain Plasticity to Promote Stroke Recovery. Front Neurol. 2020;11:554089.doi: 10.3389/fneur.2020.554089 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref014] 14.Gómez-Soria I, Iguacel I, Aguilar-Latorre A, Peralta-Marrupe P, Latorre E, Zaldívar JNC, et al. Cognitive stimulation and cognitive results in older adults: A systematic review and meta-analysis. Arch Gerontol Geriatr. 2023;104:104807.doi: 10.1016/j.archger.2022.104807 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref015] 15.Justo-Henriques SI, Pérez-Sáez E, Marques-Castro AE, Carvalho JO. Effectiveness of a year-long individual cognitive stimulation program in Portuguese older adults with cognitive impairment. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2023;30(3):321–35.doi: 10.1080/13825585.2021.2023458 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref016] 16.Hardy JL, Nelson RA, Thomason ME, Sternberg DA, Katovich K, Farzin F, et al. Enhancing Cognitive Abilities with Comprehensive Training: A Large, Online, Randomized, Active-Controlled Trial. PLoS One. 2015;10(9):e0134467.doi: 10.1371/journal.pone.0134467 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref017] 17.Snowdon DA. Healthy aging and dementia: findings from the Nun Study. Ann Intern Med. 2003;139(5 Pt 2):450–4. [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref018] 18.Iacono D, Markesbery WR, Gross M, Pletnikova O, Rudow G, Zandi P, et al. The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life. Neurology. 2009;73(9):665–73.doi: 10.1212/WNL.0b013e3181b01077 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref019] 19.Nelson ME, Jester DJ, Petkus AJ, Andel R. Cognitive Reserve, Alzheimer’s Neuropathology, and Risk of Dementia: A Systematic Review and Meta-Analysis. Neuropsychol Rev. 2021;31(2):233–50.doi: 10.1007/s11065-021-09478-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref020] 20.Maguire EA, Woollett K, Spiers HJ. London taxi drivers and bus drivers: a structural MRI and neuropsychological analysis. Hippocampus. 2006;16(12):1091–101.doi: 10.1002/hipo.20233 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref021] 21.Griesbauer E-M, Manley E, Wiener JM, Spiers HJ. London taxi drivers: A review of neurocognitive studies and an exploration of how they build their cognitive map of London. Hippocampus. 2022;32(1):3–20.doi: 10.1002/hipo.23395 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref022] 22.Boot WR, Kramer AF. The brain-games conundrum: does cognitive training really sharpen the mind?. Cerebrum. 2014;2014:15. [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref023] 23.Owen AM, Hampshire A, Grahn JA, Stenton R, Dajani S, Burns AS, et al. Putting brain training to the test. Nature. 2010;465(7299):775–8.doi: 10.1038/nature09042 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref024] 24.Gobet F, Sala G. Cognitive Training: A Field in Search of a Phenomenon. Perspect Psychol Sci. 2023;18(1):125–41.doi: 10.1177/17456916221091830 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref025] 25.Au J, Gibson BC, Bunarjo K, Buschkuehl M, Jaeggi SM. Quantifying the Difference between Active and Passive Control Groups in Cognitive Interventions Using two Meta-Analytical Approaches. J Cogn Enhanc. 2020;4(2):192–210.doi: 10.1007/s41465-020-00164-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref026] 26.Matuszewski J, Kossowski B, Bola Ł, Banaszkiewicz A, Paplińska M, Gyger L, et al. Brain plasticity dynamics during tactile Braille learning in sighted subjects: Multi-contrast MRI approach. Neuroimage. 2021;227:117613.doi: 10.1016/j.neuroimage.2020.117613 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref027] 27.Bola Ł, Siuda-Krzywicka K, Paplińska M, Sumera E, Hańczur P, Szwed M. Braille in the Sighted: Teaching Tactile Reading to Sighted Adults. PLoS One. 2016;11(5):e0155394.doi: 10.1371/journal.pone.0155394 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref028] 28.Philip BA, Frey SH. Increased functional connectivity between cortical hand areas and praxis network associated with training-related improvements in non-dominant hand precision drawing. Neuropsychologia. 2016;87:157–68.doi: 10.1016/j.neuropsychologia.2016.05.016 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref029] 29.NCD Countdown 2030 collaborators. NCD Countdown 2030: worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4. Lancet. 2018;392(10152):1072–88.doi: 10.1016/S0140-6736(18)31992-5 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref030] 30.Santos Lopes da Silva L, Tasinafo Júnior MF, da Silva Gonçalves L, Polveiro da Silva A, Pengo Almeida Leite LF, Scatena Fávero L, et al. Does Multicomponent Training Improve Cognitive Function in Older Adults Without Cognitive Impairment? A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Med Dir Assoc. 2023;24(6):765–72.doi: 10.1016/j.jamda.2023.03.004 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref031] 31.Rebok GW, Ball K, Guey LT, Jones RN, Kim H-Y, King JW, et al. Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. J Am Geriatr Soc. 2014;62(1):16–24. doi: 10.1111/jgs.12607 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref032] 32.Torralva T, Roca M, Gleichgerrcht E, Bonifacio A, Raimondi C, Manes F. Validation of the Spanish Version of the Addenbrooke’s Cognitive Examination-Revised (ACE-R). Neurologia. 2011;26(6):351–6.doi: 10.1016/j.nrl.2010.10.013 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref033] 33.Leoón, Garcića-Garcića J, Roldaán-Tapia L. Cognitive Reserve Scale and ageing. Anales de psicología. 2016;32(1):218–23. [Google Scholar]

[pone.0331193.ref034] 34.Goulet-Pelletier J-C, Cousineau D. A review of effect sizes and their confidence intervals, Part I: The Cohen’s d family. TQMP. 2018;14(4):242–65.doi: 10.20982/tqmp.14.4.p242 [DOI] [Google Scholar]

[pone.0331193.ref035] 35.R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. 2023. [Google Scholar]

[pone.0331193.ref036] 36.Hertzog C, Kramer AF, Wilson RS, Lindenberger U. Enrichment Effects on Adult Cognitive Development: Can the Functional Capacity of Older Adults Be Preserved and Enhanced? Psychol Sci Public Interest. 2008;9(1):1–65. [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref037] 37.Sporns O, Chialvo DR, Kaiser M, Hilgetag CC. Organization, development and function of complex brain networks. Trends Cogn Sci. 2004;8(9):418–25.doi: 10.1016/j.tics.2004.07.008 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref038] 38.Bassett DS, Sporns O. Network neuroscience. Nat Neurosci. 2017;20(3):353–64.doi: 10.1038/nn.4502 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0331193.ref039] 39.Anderson JR, Betts S, Bothell D, Lebiere C. Discovering skill. Cogn Psychol. 2021;129:101410.doi: 10.1016/j.cogpsych.2021.101410 [DOI] [PubMed] [Google Scholar]

[pone.0331193.ref040] 40.Siuda-Krzywicka K, Bola Ł, Paplińska M, Sumera E, Jednoróg K, Marchewka A, et al. Massive cortical reorganization in sighted Braille readers. Elife. 2016;5:e10762.doi: 10.7554/eLife.10762 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

A new program for systematically enhancing cognitive reserve in healthy adults: A pilot randomized active-controlled clinical trial

Carol Kotliar

Lisandro Olmos

Martín Koretzky

Ricardo Jauregui

Tomás Delía

Oscar Cingolani

Roles

Abstract

Objective

Background

Design

Setting

Participants

Methods

Results

Conclusions

Registration

Introduction

Objectives

Methods

Design

Fig 1. CONSORT flow diagram of participant recruitment and retention.

Ethics statement and informed consent

Participants

Table 1. Baseline characteristics by group.

Intervention description

Program delivery.

Fig 2. MTT’s structural unit defined as the combination of a new knowledge and cognitive skills for its effective learning and memorization.

Evaluations

Outcomes

Statistical analyses

Results

Changes in cognitive performance

Table 2. Effect of MTT 24.5 program on cognitive abilities outcomes.

Fig 3. A. Mean change from baseline on Cognitive Ability Scores.

Fig 4. Clinical covariates and cognitive response phenotypes.

Discussion

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Roya Khanmohammadi

Roles

Author response to Decision Letter 1

Decision Letter 1

Roya Khanmohammadi

Roles

Author response to Decision Letter 2

Decision Letter 2

Roya Khanmohammadi

Roles

Author response to Decision Letter 3

Decision Letter 3

Roya Khanmohammadi

Roles

Author response to Decision Letter 4

Decision Letter 4

Roya Khanmohammadi

Roles

Acceptance letter

Roya Khanmohammadi

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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