Examining the relationship between brain activation and proxies of disease severity using quantile regression in individuals at risk of Alzheimer's disease.

Previous studies have reported a pattern of hyperactivation in the pre-dementia phase of Alzheimer's disease (AD), followed by hypoactivation in later stages of the disease. This pattern was modeled as an inverse U-shape function between activation and markers of disease severity. In this study, we used quantile regression to model the association between task-related brain activation in AD signature regions and three markers of disease severity (hippocampal volume, cortical thickness, and associative memory). This approach offers distinct advantages over standard regression models as it analyzes the relationship between brain activation and disease severity across various levels of brain activation. Participants were 54 older adults with subjective cognitive decline+ (SCD+) or mild cognitive impairment (MCI) from the CIMA-Q cohort. The analysis revealed an inverse U-shape quadratic function depicting the relationship between disease severity markers and the activation of the left superior parietal region, while a linear relationship was observed for activation of the hippocampal and temporal regions. Quantile differences were observed for temporal and parietal activation, with more pronounced effects observed in the higher quantiles of activation. When comparing quantiles, we found that higher quantile of activation featured a greater number of individuals with SCD+ compared to mild cognitive impairment (MCI). Results are globally consistent with the presence of an inverse-U shape function of activation in relation to disease severity. They study also underscores the utility of employing quantile regression modeling as the modeling approach revealed the presence of non-homogeneous effects across various quantiles.

The SPECTRA Study: Validating a New Memory Training Program based on the Episodic Specificity Induction to Promote Transfer in Older Adults.

Some complex cognitive activities impacted by aging (future thinking, problem-solving, creative thinking) have been shown to rely on episodic retrieval, suggesting that cognitive interventions aiming to improve retrieval have the potential to induce transfer effects to these activities. Prior studies have shown that a brief one-session technique called Episodic Specificity Induction (ESI) can transiently improve episodic retrieval and induce transfer effects to complex tasks that rely on episodic retrieval in older adults. In the present proof-of-concept study, we assessed whether a training program consisting of repeated practice of the ESI technique can improve episodic retrieval and transfer to complex tasks. Fifteen healthy older adults completed a six-session intervention where they received repeated ESI practice. Before and after the intervention, nearest transfer effects were assessed using free recall, near transfer effects using recognition and associative recognition, and far-transfer effects using mean-ends problem-solving and divergent creative thinking. Before the intervention, typical ESI effects were observed (better performance after an ESI than after a control task), indicating that the ESI operated as expected in our sample. When examining the intervention effects, performance was increased after the intervention on free recall and recognition (nearest- and near-transfer) as well as problem-solving and divergent creative thinking (far transfer). These results indicate that an intervention relying on the ESI technique can produce both near and far transfer. These findings support the use of the ESI in the design of interventions that could improve retrieval and have a broad impact on a range of complex tasks.

Hippocampal Volume and Episodic Associative Memory Identify Memory Risk in Subjective Cognitive Decline Individuals in the CIMA-Q Cohort, Regardless of Cognitive Reserve Level and APOE4 Status.

BACKGROUND: Subjective cognitive decline (SCD) was proposed to identify older adults who complain about their memory but perform within a normal range on standard neuropsychological tests. Persons with SCD are at increased risk of dementia meaning that some SCD individuals experience subthreshold memory decline due to an underlying progression of Alzheimer's disease (AD). OBJECTIVE: Our main goal was to determine whether hippocampal volume and APOE4, which represent typical AD markers, predict inter-individual differences in memory performance among SCD individuals and can be used to identify a meaningful clinical subgroup. METHODS: Neuropsychological assessment, structural MRI, and genetic testing for APOE4 were administered to one hundred and twenty-five older adults over the age of 65 from the CIMAQ cohort: 66 SCD, 29 individuals with mild cognitive impairment (MCI), and 30 cognitively intact controls (CTRLS). Multiple regression models were first used to identify which factor (hippocampal volume, APOE4 allele, or cognitive reserve) best predicted inter-individual differences in a Face-name association memory task within the SCD group. RESULTS: Hippocampal volume was found to be the only and best predictor of memory performance. We then compared the demographic, clinical and cognitive characteristics of two SCD subgroups, one with small hippocampal volume (SCD/SH) and another with normal hippocampal volume (SCD/NH), with MCI and CTRLS. SCD/SH were comparable to MCI on neuropsychological tasks evaluating memory (i.e., test of delayed word recall), whereas SCD/NH were comparable to CTRLS. CONCLUSION: Thus, using hippocampal volume allows identification of an SCD subgroup with a cognitive profile consistent with a higher risk of conversion to AD.

Understanding the impact of radical changes in diet and the gut microbiota on brain function and structure: rationale and design of the EMBRACE study.

BACKGROUND: Bariatric surgery leads to profound changes in gut microbiota and dietary patterns, both of which may interact to impact gut-brain communication. Though cognitive function improves postsurgery, there is a large variability in outcomes. How bariatric surgery-induced modifications in the gut microbiota and dietary patterns influence the variability in cognitive function is still unclear. OBJECTIVES: To elucidate the associations between bariatric surgery-induced changes in dietary and gut microbiota patterns with cognition and brain structure. SETTING: University hospital. METHODS: A total of 120 adult patients (≥30 years) scheduled to undergo a primary bariatric surgery along with 60 age-, sex-, and body mass index-matched patients on the surgery waitlist will undergo assessments 3-months presurgery and 6- and 12-month postsurgery (or an equivalent time for the waitlist group). Additionally, 60 age-and sex-matched nonbariatric surgery eligible individuals will complete the presurgical assessments only. Evaluations will include sociodemographic and health behavior questionnaires, physiological assessments (anthropometrics, blood-, urine-, and fecal-based measures), neuropsychological cognitive tests, and structural magnetic resonance imaging. Cluster analyses of the dietary and gut microbiota changes will define the various dietary patterns and microbiota profiles, then using repeated measures mixed models, their associations with global cognitive and structural brain alterations will be explored. RESULTS: The coordinating study site (Centre intégré universitaire de santé et de services sociaux du Nord-de-l'Île-de-Montréal, QC, Canada), provided the primary ethical approval (Research Ethics Board#: MP-32-2022-2412). CONCLUSIONS: The insights generated from this study can be used to develop individually-targeted neurodegenerative disease prevention strategies, as well as providing critical mechanistic information.

Activation changes induced by cognitive training are consistent with improved cognitive reserve in older adults with subjective cognitive decline.

Functional magnetic resonance imaging (fMRI) was used to assess the effect of cognitive training on brain activation as a function of the learning phase and level of education. Forty older adults with subjective cognitive decline (SCD) received 6 1-hour memory training sessions with the method of loci. Brain imaging (N = 29) was measured during word list encoding and retrieval before training (PRE), after 3 training sessions (POST3), and after 6 training sessions (POST6). Participants showed increased activation of the left inferior pre-frontal gyrus from PRE to POST6 during encoding and reduced bilateral frontostriatal activation from PRE to POST3 during retrieval, regardless of education. Activation changes from PRE to POST3 varied as a function of education in 2 regions of the right temporal lobe: participants with lower education showed increased activation, while those with higher education showed decreased activation. These regions were initially less active in people with lower education. Results suggest a strategic shift in people with lower education and expertise building in those with higher education, along with a restoration of initial education-related differences.

Sex differences in patterns of associative memory-related activation in individuals at risk of Alzheimer's disease.

The risk of developing Alzheimer's disease dementia is higher in females compared to males and is greater in individuals with subjective cognitive decline and mild cognitive impairment than in healthy controls. We used a multivariate behavioral partial least square correlation analysis to examine how relationships between memory-related activation and associative memory performance vary as a function of sex and clinical status. This was assessed in 182 participants from the Consortium for the Early Identification of Alzheimer's Disease-Quebec cohort, which were stratified according to sex (Male, Female) and clinical status (healthy controls, subjective cognitive decline, mild cognitive impairment). We found 6 significant latent variables mainly expressing: (1) overall sex differences; (2) between-sex differences according to clinical status; and (3) within-sex differences according to clinical status in relationships between whole-brain memory-related activation and memory performance. These patterns of activation mostly involved the default mode and fronto-parietal networks. Our results have implication in understanding the macro-scale functional processes possibly contributing to the higher risk of cognitive decline in females compared to males in the context of aging and early Alzheimer's disease.

More flexible brain activation underlies cognitive reserve in older adults.

The goal of this study was to identify the brain mechanisms underlying cognitive reserve using a parametric n-back working memory (WM) task in a sample of healthy older adults. We first identified the WM-related activations associated with years of education and then tested whether these activations mitigated the detrimental impact of age on cognition. Thirty-nine older adults received a magnetic resonance imaging examination while completing an n-back task with different levels of WM load (0-, 1- vs. 2-back). Results show that more education is associated with lower activation of the left medial superior frontal gyrus (BA8) in the 1-back condition and a greater activation of the right caudate nucleus in the 2-back condition. The caudate and frontal activations are task-positive and task-negative regions, respectively. Moderation analyses indicate that the effect of age on performance is less detrimental in participants with higher caudate activation in the 2-back condition. Overall, these results suggest that cognitive reserve is explained by a superior ability to flexibly engage greater or novel activation as cognitive demand increases.

Is more always better? Dose effect in a multidomain intervention in older adults at risk of dementia.

BACKGROUND: Little is known regarding the dose-response function in multidomain interventions for dementia prevention. METHOD: The Multidomain Alzheimer Preventive Trial is a 3-year randomized controlled trial comprising cognitive training, physical activity, nutrition, and omega-3 polyunsaturated fatty acids for at-risk older adults. The dose delivered (number of sessions attended) was modeled against global cognition, memory, and fluency in 749 participants. Interaction effects were assessed for age, sex, education, dementia score (CAIDE), frailty score, and apolipoprotein E (APOE) ε4 status. RESULTS: The dose-response models were non-linear functions indicating benefits up to about 12 to 14 training hours or 15 to 20 multidomain sessions followed by a plateau. Participants who benefited from a higher dose included women, younger participants, frail individuals, and those with lower education or lower risk of dementia. DISCUSSION: The non-linear function indicates that a higher dose is not necessarily better in multidomain interventions. The optimal dose was about half of the potentially available sessions.

Having a stimulating lifestyle is associated with maintenance of white matter integrity with age.

Brain maintenance refers to the fact that some older adults experience few age-related changes in the brain, which helps maintain their cognition. The goal of this study was to assess maintenance of white matter integrity by testing whether reserve proxies, measuring factors associated to a stimulating lifestyle, affect the maintenance of white matter integrity. Another goal was to measure whether maintenance of white matter integrity explains inter-individual differences in working memory (WM). Forty-one cognitively healthy older adults received a structural magnetic resonance imaging (MRI) examination to measure white matter lesions. They completed an n-back WM task with different loads (1- & 2-back), along with a questionnaire on their lifestyle. There was a positive association between age and volume of white matter lesions. This association was no longer found in those with higher scores on reserve proxies. In addition, smaller volumes of white matter lesions were associated with better performance than expected for age in the 1-back WM task. Better WM is associated with the maintenance of white matter integrity in older adults, which in turn is linked to measures reflecting a stimulating lifestyle throughout life.

Latent patterns of task-related functional connectivity in relation to regions of hyperactivation in individuals at risk of Alzheimer's disease.

The goal of this study was to assess how task-related hyperactivation relates to brain network dysfunction and memory performance in individuals at risk of Alzheimer's disease (AD). Eighty participants from the CIMA-Q cohort were included, of which 28 had subjective cognitive decline plus (SCD+), as they had memory complaints and worries in addition to a smaller hippocampal volume and/or an APOE4 allele, 26 had amnestic mild cognitive impairment (MCI) and 26 were healthy controls without memory complaints. Functional magnetic resonance imaging (fMRI) activation was measured during an object-location memory task. Seed-partial least square analyses (seed-PLS) were conducted in controls and in the SCD+/MCI groups to yield sets of orthogonal latent variables (LVs) assessing the triple association between: i) seed activity in brain regions found to be hyperactive in individuals at risk of AD (left hippocampus, left superior parietal lobule, right inferior temporal lobe), ii) latent patterns of whole-brain task-related activation, and iii) associative memory performance. Three LVs in the SCD+ and MCI groups (67.88% of total covariance explained) and two LVs in the controls (77.85% of total covariance explained) were significant. While controls and SCD+/MCI groups shared a common pattern of memory-related connectivity, patterns of hyperactivation-networks interactions were unique to the clinical groups. Interestingly, higher hippocampal connectivity was associated with poorer memory performance whereas higher neocortical connectivity predicted better memory performance in SCD+ and MCI groups. Our data provides empirical evidence that early dysfunction in brain activation and connectivity is present in the very early stages of AD and offers new insights on the relationship between functional brain alterations and memory performance.

Neural correlates of resilience to the effects of hippocampal atrophy on memory.

INTRODUCTION: Cognitive reserve can be defined as a property of the brain that enables an individual to sustain cognitive performance in spite of age-related neural changes. This study uses brain imaging to identify which cognitive reserve mechanisms protect against the detrimental effect of hippocampal atrophy on associative memory. METHODS: The study included 108 older adults from the Quebec Consortium for the early identification of Alzheimer's disease. They received a magnetic resonance imaging examination to measure memory-related activations and hippocampal volume. Participants also completed a reserve-proxy questionnaire, and received a comprehensive clinical assessment. RESULTS: Higher scores on the reserve questionnaire were associated with more activation in the right inferior temporal and left occipital fusiform gyri. The activation of the right temporal gyrus moderated the relationship between the volume of the hippocampus and face-name memory. A smaller volume was associated with weaker memory in participants with lower activation, but not in those with greater activation. DISCUSSION: Recruitment of the temporal lobe protects against the detrimental effect of hippocampal atrophy on associative memory and contributes to cognitive reserve.

Effects of Computerized Updating and Inhibition Training in Older Adults: The ACTOP Three-Arm Randomized Double-Blind Controlled Trial.

Background: Working memory (WM) capacity declines with advancing age, which impacts the ability to carry out complex cognitive activities in everyday life. Updating and inhibition processes have been identified as some of the most critical attentional control processes of WM and are linked to age-related WM decline. The general aim of the Attentional Control Training in Older People (ACTOP) study was to perform a side-by-side comparison of updating and inhibition training to examine their respective efficacy and transfer in cognitively healthy older adults. Method: The study was a three-arm, double-blind, randomized controlled trial registered with the US National Institutes of Health clinical trials registry. Ninety older adults were randomly assigned to 12 half-hour sessions of updating (N-back type exercises), inhibition (Stroop-like exercises) computerized training or active control (general knowledge quiz game). A group of thirty younger adults completed all proximal and WM transfer tasks without training to assess age-related deficits prior to training and whether training reduces these deficits. Results: Piecewise mixed models show quick improvement of performance during training for both updating and inhibition training. During updating training, the progression was more pronounced for the most difficult (3-back) than for the least (1-back) difficult level until the ninth session. Updating and inhibition training groups improved performance on all proximal and WM transfer measures but these improvements did not differ from the active control group. Younger adults outperformed older ones on all transfer tasks prior to training. However, this was no longer the case following training for two transfer tasks regardless of the training group. Conclusion: The overall results from this study suggest that attentional control training is effective in improving updating and inhibition performance on training tasks. The optimal dose to achieve efficacy is ~9 half-hour sessions and the dose effect was related to difficulty level for updating training. Despite an overall improvement of older adults on all transfer tasks, neither updating nor inhibition training provided additional improvements in comparison with the active control condition. This suggests that the efficacy of process-based training does not directly affect transfer tasks. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03532113.

Assessing the Effect of Training on the Cognition and Brain of Older Adults: Protocol for a Three-Arm Randomized Double-Blind Controlled Trial (ACTOP).

BACKGROUND: To prevent age-related cognitive impairment, many intervention programs offer exercises targeting different central cognitive processes. However, the effects of different process-based training programs are rarely compared within equivalent experimental designs. OBJECTIVE: Using a randomized double-blind controlled trial, this project aims to examine and compare the impact of 2 process-based interventions, inhibition and updating, on the cognition and brain of older adults. METHODS: A total of 90 healthy older adults were randomly assigned to 1 of 3 training conditions: (1) inhibition (Stroop-like exercises), (2) updating (N-back-type exercises), and (3) control active (quiz game exercise). Training was provided in 12 half-hour sessions over 4 weeks. First, the performance gain observed will be measured on the trained tasks. We will then determine the extent of transfer of gain on (1) untrained tasks that rely on the same cognitive process, (2) complex working memory (WM) measurements hypothesized to involve 1 of the 2 trained processes, and (3) virtual reality tasks that were designed to mimic real-life situations that require WM. We will assess whether training increases cortical volume given that the volume of the cortex is determined by cortical area and thickness in regions known to be involved in WM or changes task-related brain activation patterns measured with functional magnetic resonance imaging. Dose effects will be examined by measuring outcomes at different time points during training. We will also determine whether individual characteristics moderate the effect of training on cognitive and cerebral outcomes. Finally, we will evaluate whether training reduces the age-related deficit on transfer and brain outcomes, by comparing study participants to a group of 30 younger adults. RESULTS: The project was funded in January 2017; enrollment began in October 2017 and data collection was completed in April 2019. Data analysis has begun in June 2020 and the first results should be published by the end of 2020 or early 2021. CONCLUSIONS: The results of this study will help understand the relative efficacy of 2 attentional control interventions on the cognition and the brain of older adults, as well as the moderating role of individual characteristics on training efficiency and transfer. TRIAL REGISTRATION: ClinicalTrials.gov NCT03532113; https://clinicaltrials.gov/ct2/show/NCT03532113. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/20430.

A quadratic function of activation in individuals at risk of Alzheimer's disease.

INTRODUCTION: Brain activation is hypothesized to form an inverse U-shape in prodromal Alzheimer's disease (AD), with hyperactivation in the early phase, followed by hypoactivation. METHODS: Using task-related functional magnetic resonance imaging (fMRI), we tested the inverse U-shape hypothesis with polynomial regressions and between-group comparisons in individuals with subjective cognitive decline plus (SCD+; smaller hippocampal volumes compared to a group of healthy controls without SCD and/or apolipoprotein E [APOE] ε4 allele) or mild cognitive impairment (MCI). RESULTS: A quadratic function modeled the relationship between proxies of disease severity (neurodegeneration, memory performance) and left superior parietal activation. Linear negative functions modeled the relationship between neurodegeneration and left hippocampal/right inferior temporal activation. Group comparison indicated presence of hyperactivation in SCD+ and hypoactivation in MCI in the left superior parietal lobule, relative to healthy controls. DISCUSSION: These findings support the presence of an inverse U-shape model of activation and suggest that hyperactivation might represent a biomarker of the early AD stages.

Evidence of a Relation Between Hippocampal Volume, White Matter Hyperintensities, and Cognition in Subjective Cognitive Decline and Mild Cognitive Impairment.

OBJECTIVE: The concepts of mild cognitive impairment (MCI) and subjective cognitive decline (SCD) have been proposed to identify individuals in the early stages of Alzheimer's disease (AD), or other neurodegenerative diseases. One approach to validate these concepts is to investigate the relationship between pathological brain markers and cognition in those individuals. METHOD: We included 126 participants from the Consortium for the Early Identification of Alzheimer's disease-Quebec (CIMA-Q) cohort (67 SCD, 29 MCI, and 30 cognitively healthy controls [CH]). All participants underwent a complete cognitive assessment and structural magnetic resonance imaging. Group comparisons were done using cognitive data, and then correlated with hippocampal volumes and white matter hyperintensities (WMHs). RESULTS: Significant differences were found between participants with MCI and CH on episodic and executive tasks, but no differences were found when comparing SCD and CH. Scores on episodic memory tests correlated with hippocampal volumes in both MCI and SCD, whereas performance on executive tests correlated with WMH in all of our groups. DISCUSSION: As expected, the SCD group was shown to be cognitively healthy on tasks where MCI participants showed impairment. However, SCD's hippocampal volume related to episodic memory performances, and WMH to executive functions. Thus, SCD represents a valid research concept and should be used, alongside MCI, to better understand the preclinical/prodromal phase of AD.

Evidence of parietal hyperactivation in individuals with mild cognitive impairment who progressed to dementia: A longitudinal fMRI study.

Hyperactivation, which is defined as a higher level of activation in patients compared to cognitively unimpaired older adults (controls; CTL), might represent an early signature of Alzheimer's Disease (AD). The goal of this study was to assess the presence and location of hyperactivation in individuals with mild cognitive impairment (MCI) who were later diagnosed with dementia, examine how hyperactivation changes longitudinally, and whether it is related to time before dementia. Forty participants, 26 with MCI and 14 CTL were enrolled in the study. Magnetic resonance imaging was used to measure functional activation while participants encoded word-pairs as well as cortical thickness and regional brain volume at study entry (Y0) and two years later (Y2). Clinical follow-up was completed every two years following study entry to identify progressors (pMCI), that is, individuals who later received a diagnosis of dementia. Task-related activation was assessed in pMCI in both hippocampi and in regions showing greater cortical thinning from Y0 to Y2 compared to CTLs. Hyperactivation was found in pMCI individuals in the right supramarginal gyrus. Persons with pMCI also showed hypoactivation in the left hippocampus and left pars opercularis. Both hyper- and hypoactivation were present at Y0 and Y2 and did not change longitudinally. Activation was not associated with time before dementia diagnosis. Smaller volume and thinner cortical thickness were associated with shorter time to diagnosis in the left hippocampus and left pars opercularis. In conclusion, hyperactivation was found in individuals who later progressed to dementia, confirming that it might represent an early biomarker to identify individuals in the prodromal phase of AD and that its understanding could contribute to elucidate the key brain mechanisms that precede dementia.

Relationships between years of education, regional grey matter volumes, and working memory-related brain activity in healthy older adults.

The aim of this study was to examine the relationships between educational attainment, regional grey matter volume, and functional working memory-related brain activation in older adults. The final sample included 32 healthy older adults with 8 to 22 years of education. Structural magnetic resonance imaging (MRI) was used to measure regional volume and functional MRI was used to measure activation associated with performing an n-back task. A positive correlation was found between years of education and cortical grey matter volume in the right medial and middle frontal gyri, in the middle and posterior cingulate gyri, and in the right inferior parietal lobule. The education by age interaction was significant for cortical grey matter volume in the left middle frontal gyrus and in the right medial cingulate gyrus. In this region, the volume loss related to age was larger in the low than high-education group. The education by age interaction was also significant for task-related activity in the left superior, middle and medial frontal gyri due to the fact that activation increased with age in those with higher education. No correlation was found between regions that are structurally related with education and those that are functionally related with education and age. The data suggest a protective effect of education on cortical volume. Furthermore, the brain regions involved in the working memory network are getting more activated with age in those with higher educational attainment.

The impact of attentional training on event-related potentials in older adults.

Attentional control declines in older adults and is paralleled by changes in event-related brain potentials (ERPs). The N200 is associated with attentional control, thus training-related improvements in attentional control should be paralleled by enhancements to the N200. Older participants were randomly assigned to 1 of 3 groups, which focused on training different levels of attentional control: (1) single-task training (single), where participants trained on 2 tasks in isolation; (2) fixed divided attention training (fixed), where participants trained on 2 tasks simultaneously; and (3) variable divided attention training (variable), where participants trained on 2 tasks simultaneously but were instructed to alternatively prioritize each of the 2 tasks. After training, the amplitude of the N200 wave increased in dual-task conditions for the variable group, and this enhancement was correlated with improved dual-task performance. Participants in the variable group also had the greatest improvement in the ability to modulate their allocation of attention in accordance with task instructions to the less salient and less complex of the 2 tasks. Training older adults to modulate their division of attention between tasks improves neural functions associated with attentional control of the trained tasks.

The pattern and loci of training-induced brain changes in healthy older adults are predicted by the nature of the intervention.

There is enormous interest in designing training methods for reducing cognitive decline in healthy older adults. Because it is impaired with aging, multitasking has often been targeted and has been shown to be malleable with appropriate training. Investigating the effects of cognitive training on functional brain activation might provide critical indication regarding the mechanisms that underlie those positive effects, as well as provide models for selecting appropriate training methods. The few studies that have looked at brain correlates of cognitive training indicate a variable pattern and location of brain changes--a result that might relate to differences in training formats. The goal of this study was to measure the neural substrates as a function of whether divided attentional training programs induced the use of alternative processes or whether it relied on repeated practice. Forty-eight older adults were randomly allocated to one of three training programs. In the single repeated training, participants practiced an alphanumeric equation and a visual detection task, each under focused attention. In the divided fixed training, participants practiced combining verification and detection by divided attention, with equal attention allocated to both tasks. In the divided variable training, participants completed the task by divided attention, but were taught to vary the attentional priority allocated to each task. Brain activation was measured with fMRI pre- and post-training while completing each task individually and the two tasks combined. The three training programs resulted in markedly different brain changes. Practice on individual tasks in the single repeated training resulted in reduced brain activation whereas divided variable training resulted in a larger recruitment of the right superior and middle frontal gyrus, a region that has been involved in multitasking. The type of training is a critical factor in determining the pattern of brain activation.