Physical activity-related individual differences in functional human connectome are linked to fluid intelligence in older adults.

The study examined resting state functional connectivity (rs-FC) associated with moderate-to-vigorous physical activity (MV-PA), sedentary time (ST), TV viewing, computer use, and their relationship to cognitive performance in older adults. We used pre-intervention data from 119 participants from the Fit & Active Seniors trial. Multivariate pattern analysis revealed two seeds associated with MV-PA: right superior frontal gyrus (SFG; spanning frontoparietal [FPN] and ventral attention networks [VAN]) and right precentral (PrG) and postcentral gyri (PoG) of the somatosensory network (SN). A positive correlation between the right SFG seed and a cluster spanning default mode (DMN), dorsal attention (DAN), FPN, and visual networks (VIS) was linked to higher fluid intelligence, as was FC between the right PrG/PoG seed and a cluster in VIS. No significant rs-FC patterns associated with ST, TV viewing, or computer use were found. Our findings suggest that greater functional integration within networks implementing top-down control and within those supporting visuospatial abilities, paired with segregation between networks critical and those not critical to top-down control, may help promote cognitive reserve in more physically active seniors.

Musical Experience Relates to Insula-Based Functional Connectivity in Older Adults.

Engaging in musical activities throughout the lifespan may protect against age-related cognitive decline and modify structural and functional connectivity in the brain. Prior research suggests that musical experience modulates brain regions that integrate different modalities of sensory information, such as the insula. Most of this research has been performed in individuals classified as professional musicians; however, general musical experiences across the lifespan may also confer beneficial effects on brain health in older adults. The current study investigated whether general musical experience, characterized using the Goldsmith Music Sophistication Index (Gold-MSI), was associated with functional connectivity in older adults (age = 65.7 ± 4.4, n = 69). We tested whether Gold-MSI was associated with individual differences in the functional connectivity of three a priori hypothesis-defined seed regions in the insula (i.e., dorsal anterior, ventral anterior, and posterior insula). We found that older adults with more musical experience showed greater functional connectivity between the dorsal anterior insula and the precentral and postcentral gyrus, and between the ventral anterior insula and diverse brain regions, including the insula and prefrontal cortex, and decreased functional connectivity between the ventral anterior insula and thalamus (voxel p < 0.01, cluster FWE p < 0.05). Follow-up correlation analyses showed that the singing ability subscale score was key in driving the association between functional connectivity differences and musical experience. Overall, our findings suggest that musical experience, even among non-professional musicians, is related to functional brain reorganization in older adults.

The Differential Effects of Adiposity and Fitness on Functional Connectivity in Preadolescent Children.

PURPOSE: Childhood obesity is a global health concern, with >340 million youth considered overweight or obese. In addition to contributing greatly to health care costs, excess adiposity associated with obesity is considered a major risk factor for premature mortality from cardiovascular and metabolic diseases and is also negatively associated with cognitive and brain health. A complementary line of research highlights the importance of cardiorespiratory fitness, a by-product of engaging in physical activity, on an abundance of health factors, including cognitive and brain health. METHODS: This study investigated the relationship among excess adiposity (visceral adipose tissue [VAT], subcutaneous abdominal adipose tissue), total abdominal adipose tissue, whole-body percent fat [WB%FAT], body mass index (BMI), and fat-free cardiorespiratory fitness (FF-V̇O 2max ) on resting-state functional connectivity (RSFC) in 121 ( f = 68) children (7-11 yr) using a data-driven whole-brain multivoxel pattern analysis. RESULTS: Multivoxel pattern analysis revealed brain regions that were significantly associated with VAT, BMI, WB%FAT, and FF-V̇O 2 measures. Yeo's (2011) RSFC-based seven-network cerebral cortical parcellation was used for labeling the results . Post hoc seed-to-voxel analyses found robust negative correlations of VAT and BMI with areas involved in the visual, somatosensory, dorsal attention, ventral attention, limbic, frontoparietal, and default mode networks. Further, positive correlations of FF-V̇O 2 were observed with areas involved in the ventral attention and frontoparietal networks. These novel findings indicate that negative health factors in childhood may be selectively and negatively associated with the 7 Yeo-defined functional networks, yet positive health factors (FF-V̇O 2 ) may be positively associated with these networks. CONCLUSIONS: These novel results extend the current literature to suggest that BMI and adiposity are negatively associated with, and cardiorespiratory fitness (corrected for fat-free mass) is positively associated with, RSFC networks in children.

Brain network modularity predicts changes in cortical thickness in children involved in a physical activity intervention.

Individual differences in brain network modularity at baseline can predict improvements in cognitive performance after cognitive and physical interventions. This study is the first to explore whether brain network modularity predicts changes in cortical brain structure in 8- to 9-year-old children involved in an after-school physical activity intervention (N = 62), relative to children randomized to a wait-list control group (N = 53). For children involved in the physical activity intervention, brain network modularity at baseline predicted greater decreases in cortical thickness in the anterior frontal cortex and parahippocampus. Further, for children involved in the physical activity intervention, greater decrease in cortical thickness was associated with improvements in cognitive efficiency. The relationships among baseline modularity, changes in cortical thickness, and changes in cognitive performance were not present in the wait-list control group. Our exploratory study has promising implications for the understanding of brain network modularity as a biomarker of intervention-related improvements with physical activity.

Enriching activities during childhood are associated with variations in functional connectivity patterns later in life.

Enriching early life experiences (e.g., sport, art, music, volunteering, language learning) during a critical period of brain development may promote structural and functional brain changes that are still present decades later (>60 years). We assessed whether a greater variety of enriching early life activities (EELA) before age 13 years were associated with individual differences in cortical and subcortical (hippocampus and amygdala) structure and function later in life (older adults aged 60-80 years). Results indicated no association between EELA and amygdala and hippocampus volumes, but higher functional connectivity between the amygdala and the insula was associated with more variety of EELA. EELA was not associated with cortical thickness controlling for sex, but sex-specific associations with the right pars opercularis were found. EELA was further associated with variations in functional connectivity patterns of the orbitofrontal cortex, driven by connecitivty to regions within the visual, somatosensory and limbic networks. Early life enriching activities appear to contribute to potential mechanisms of cognitive reserve (functional processes) more so than brain reserve (structure) later in life.

Musical Training and Brain Volume in Older Adults.

Musical practice, including musical training and musical performance, has been found to benefit cognitive function in older adults. Less is known about the role of musical experiences on brain structure in older adults. The present study examined the role of different types of musical behaviors on brain structure in older adults. We administered the Goldsmiths Musical Sophistication Index, a questionnaire that includes questions about a variety of musical behaviors, including performance on an instrument, musical practice, allocation of time to music, musical listening expertise, and emotional responses to music. We demonstrated that musical training, defined as the extent of musical training, musical practice, and musicianship, was positively and significantly associated with the volume of the inferior frontal cortex and parahippocampus. In addition, musical training was positively associated with volume of the posterior cingulate cortex, insula, and medial orbitofrontal cortex. Together, the present study suggests that musical behaviors relate to a circuit of brain regions involved in executive function, memory, language, and emotion. As gray matter often declines with age, our study has promising implications for the positive role of musical practice on aging brain health.

Relationships between enriching early life experiences and cognitive function later in life are mediated by educational attainment.

The study of how engagement in enriching cognitive, physical and social activities in childhood impacts cognitive function decades later will advance our understanding of how modifiable lifestyle activities promote cognition across the lifespan. 88 healthy older adults (aged 60-80 years) returned a retrospective questionnaire regarding their participation in seven lifestyle activities (musical instrument playing, language learning, sport participation, art/dance lessons, scouting, volunteering, family vacations) before age 13 years. After controlling for current age, educational attainment, socioeconomic status of the mother and current engagement in lifestyle activities, a greater number of activities were significantly associated with better vocabulary abilities, episodic memory and fluid intelligence. The relationships with vocabulary and fluid intelligence were mediated by educational attainment. We postulate that engagement in a higher number of enriching early life activities is a reflection of both one's sociocontextual environment and engagement with that environment. This engagement leads to attributes relevant for educational aspirations/attainment, ultimately contributing to factors that have a lifespan impact on cognitive function.

Resting-State Functional Connectivity and Scholastic Performance in Preadolescent Children: A Data-Driven Multivoxel Pattern Analysis (MVPA).

Scholastic performance is the key metric by which schools measure student's academic success, and it is important to understand the neural-correlates associated with greater scholastic performance. This study examines resting-state functional connectivity (RsFc) associated with scholastic performance (reading and mathematics) in preadolescent children (7-9 years) using an unbiased whole-brain connectome-wide multi-voxel pattern analysis (MVPA). MVPA revealed four clusters associated with reading composite score, these clusters were then used for whole-brain seed-based RsFc analysis. However, no such clusters were found for mathematics composite score. Post hoc analysis found robust associations between reading and RsFc dynamics with areas involved with the somatomotor, dorsal attention, ventral attention, limbic, frontoparietal, and default mode networks. These findings indicate that reading ability may be associated with a wide range of RsFc networks. Of particular interest, anticorrelations were observed between the default mode network and the somatomotor, dorsal attention, ventral attention, and frontoparietal networks. Previous research has demonstrated the importance of anticorrelations between the default mode network and frontoparietal network associated with cognition. These results extend the current literature exploring the role of network connectivity in scholastic performance of children.

Brain Network Modularity Predicts Improvements in Cognitive and Scholastic Performance in Children Involved in a Physical Activity Intervention.

Introduction: Brain network modularity is a principle that quantifies the degree to which functional brain networks are divided into subnetworks. Higher modularity reflects a greater number of within-module connections and fewer connections between modules, and a highly modular brain is often interpreted as a brain that contains highly specialized brain networks with less integration between networks. Recent work in younger and older adults has demonstrated that individual differences in brain network modularity at baseline can predict improvements in performance after cognitive and physical interventions. The use of brain network modularity as a predictor of training outcomes has not yet been examined in children. Method: In the present study, we examined the relationship between baseline brain network modularity and changes (post-intervention performance minus pre-intervention performance) in cognitive and academic performance in 8- to 9-year-old children who participated in an after-school physical activity intervention for 9 months (N = 78) as well as in children in a wait-list control group (N = 72). Results: In children involved in the after-school physical activity intervention, higher modularity of brain networks at baseline predicted greater improvements in cognitive performance for tasks of executive function, cognitive efficiency, and mathematics achievement. There were no associations between baseline brain network modularity and performance changes in the wait-list control group. Discussion: Our study has implications for biomarkers of cognitive plasticity in children. Understanding predictors of cognitive performance and academic progress during child development may facilitate the effectiveness of interventions aimed to improve cognitive and brain health.

Musical Instrument Practice Predicts White Matter Microstructure and Cognitive Abilities in Childhood.

Musical training has been associated with advantages in cognitive measures of IQ and verbal ability, as well as neural measures including white matter microstructural properties in the corpus callosum (CC) and the superior longitudinal fasciculus (SLF). We hypothesized that children who have musical training will have different microstructural properties in the SLF and CC. One hundred children aged 7.9-9.9 years (mean age 8.7) were surveyed for their musical activities, completed neuropsychological testing for general cognitive abilities, and underwent diffusion tensor imaging (DTI) as part of a larger study. Children who play a musical instrument for more than 0.5 h per week (n = 34) had higher scores on verbal ability and intellectual ability (standardized scores from the Woodcock-Johnson Tests of Cognitive Abilities), as well as higher axial diffusivity (AD) in the left SLF than those who did not play a musical instrument (n = 66). Furthermore, the intensity of musical practice, quantified as the number of hours of music practice per week, was correlated with axial diffusivity (AD) in the left SLF. Results are not explained by age, sex, socio-economic status, or physical fitness of the participants. The results suggest that the relationship between musical practice and intellectual ability is related to the maturation of white matter pathways in the auditory-motor system. The findings suggest that musical training may be a means of improving cognitive and brain health during development.

Physical Fitness, White Matter Volume and Academic Performance in Children: Findings From the ActiveBrains and FITKids2 Projects.

Objectives: The aims of this study were (i) to examine the association between cardiorespiratory fitness and white matter volume and test whether those associations differ between normal-weight and overweight/obese children (ii) to analyze the association between other physical fitness components (i.e., motor and muscular) and white matter volume, and (iii) to examine whether the fitness-related associations in white matter volume were related to academic performance. Methods: Data came from two independent projects: ActiveBrains project (n = 100; 10.0 ± 1.1 years; 100% overweight/obese; Spain) and FITKids2 project (n = 242; 8.6 ± 0.5 years; 36% overweight/obese, United States). Cardiorespiratory fitness was assessed in both projects, and motor and muscular fitness were assessed in the ActiveBrains project. T1-weighted images were acquired with a 3.0 T S Magnetom Tim Trio system. Academic performance was assessed by standardized tests. Results: Cardiorespiratory fitness was associated with greater white matter volume in the ActiveBrain project (P < 0.001, k = 177; inferior fronto-opercular gyrus and inferior temporal gyrus) and in the FITKids project (P < 0.001, k = 117; inferior temporal gyrus, cingulate gyrus, middle occipital gyrus and fusiform gyrus) among overweight/obese children. However, no associations were found among normal-weight children in the FITKids project. In the ActiveBrains project, motor fitness was related to greater white matter volume (P < 0.001, k = 173) in six regions, specifically, insular cortex, caudate, bilateral superior temporal gyrus and bilateral supramarginal gyrus; muscular fitness was associated with greater white matter volumes (P < 0.001, k = 191) in two regions, particularly, the bilateral caudate and bilateral cerebellum IX. The white matter volume of six of these regions were related to academic performance, but after correcting for multiple comparisons, only the insular cortex remained significantly related to math calculations skills (ß = 0.258; P < 0.005). In both projects, no brain regions showed a statistically significant negative association between any physical fitness component and white matter volume. Conclusion: Cardiorespiratory fitness may positively relate to white matter volume in overweight/obese children, and in turn, academic performance. In addition, motor and muscular fitness may also influence white matter volume coupled with better academic performance. From a public health perspective, implementing exercise interventions that combine aerobic, motor and muscular training to enhance physical fitness may benefit brain development and academic success.

The Associations between Adiposity, Cognitive Function, and Achievement in Children.

Although obesity has been related to measures of academic achievement and cognition in children, the influence of fat distribution, specifically visceral adiposity, on select aspects of achievement and cognitive function remains poorly characterized among preadolescent children. PURPOSE: The aim of this study was to evaluate the relation of adiposity, particularly visceral adipose tissue (VAT), on achievement and cognitive function among children. METHODS: Children with obesity (ages 8-9 yr old, N = 55, 35 females) completed cognitive and academic tests. Normal weight children (N = 55, 35 females) were matched to this group on demographic characteristics and aerobic fitness. Covariate analyses included age, Brief Intellectual Ability, socioeconomic status, and fat-free V˙O2 (V˙O2 peak adjusted for lean mass; mL·kg lean·min). Adiposity (i.e., whole body percent fat, subcutaneous abdominal adipose tissue, and VAT) was assessed using dual-energy x-ray absorptiometry. RESULTS: The results of this study revealed that, relative to their normal weight counterparts, children with obesity had significantly lower performance on tests of reading and math. Analyses revealed that among children with obesity, %Fat and subcutaneous abdominal adipose tissue were not related to cognitive abilities. However, higher VAT was associated with poorer intellectual abilities (Ps ≤ 0.04) and cognitive performance (i.e., thinking ability and cognitive efficiency, Ps ≤ 0.04). However, among normal weight children, VAT was positively associated with intellectual abilities and cognitive efficiency. CONCLUSION: In conclusion, the results suggest that VAT was selectively and negatively related with cognition among children with obesity. Along with the dangerous metabolic nature of VAT, its detrimental relationship with obese children's intellectual and cognitive functioning is concerning.

Scholastic performance and functional connectivity of brain networks in children.

One of the keys to understanding scholastic success is to determine the neural processes involved in school performance. The present study is the first to use a whole-brain connectivity approach to explore whether functional connectivity of resting state brain networks is associated with scholastic performance in seventy-four 7- to 9-year-old children. We demonstrate that children with higher scholastic performance across reading, math and language have more integrated and interconnected resting state networks, specifically the default mode network, salience network, and frontoparietal network. To add specificity, core regions of the dorsal attention and visual networks did not relate to scholastic performance. The results extend the cognitive role of brain networks in children as well as suggest the importance of network connectivity in scholastic success.

Physical Activity Increases White Matter Microstructure in Children.

Children are becoming increasingly inactive, unfit, and overweight, yet there is relatively little causal evidence regarding the effects of physical activity on brain health during childhood. The present study examined the effects of an after-school physical activity program (FITKids2) on the microstructure of white matter tracts in 7- to 9-year-old children. We measured the microstructural properties of white matter via diffusion tensor imaging in 143 children before and after random assignment to either a 9-month after-school physical activity program (N = 76, mean age = 8.7 years) or a wait list control group (N = 67, mean age = 8.7 years). Our results demonstrate that children who participated in the physical activity program showed increased white matter microstructure in the genu of the corpus callosum, with no changes in white matter microstructure in the wait list control group which reflects typical development. Specifically, children in the physical activity program showed increases in fractional anisotropy (FA) and decreases in radial diffusivity (RD) in the genu from pre- to post-test, thereby suggesting more tightly bundled and structurally compact fibers (FA) and increased myelination (RD), with no changes in estimates of axonal fiber diameter (axial diffusivity, AD). The corpus callosum integrates cognitive, motor, and sensory information between the left and right hemispheres of the brain, and the white matter tract plays a role in cognition and behavior. Our findings reinforce the importance of physical activity for brain health during child development.

Regional Brain Volumes Moderate, but Do Not Mediate, the Effects of Group-Based Exercise Training on Reductions in Loneliness in Older Adults.

Introduction: Despite the prevalence of and negative health consequences associated with perceived loneliness in older adults, few studies have examined interactions among behavioral, psychosocial, and neural mechanisms. Research suggests that physical activity and improvements in perceived social support and stress are related to reductions in loneliness. Yet, the influence of brain structure on these changes is unknown. The present study examined whether change in regional brain volume mediated the effects of changes in social support and stress on change in perceived loneliness after an exercise intervention. We also examined the extent to which baseline brain volumes moderated the relationship between changes in social support, stress, and loneliness. Methods: Participants were 247 older adults (65.4 ± 4.6 years-old) enrolled in a 6-month randomized controlled trial comprised of four exercise conditions: Dance (n = 69), Strength/Stretching/Stability (n = 70), Walk (n = 54), and Walk Plus (n = 54). All groups met for 1 h, three times weekly. Participants completed questionnaires assessing perceived social support, stress, and loneliness at baseline and post-intervention. Regional brain volumes (amygdala, prefrontal cortex [PFC], hippocampus) before and after intervention were measured with automatic segmentation of each participant's T1-weighted structural MRI. Data were analyzed in a latent modeling framework. Results: Perceived social support increased (p = 0.003), while stress (p < 0.001), and loneliness (p = 0.001) decreased over the intervention. Increased social support directly (-0.63, p < 0.01) and indirectly, through decreased stress (-0.10, p = 0.02), predicted decreased loneliness. Changes in amygdala, PFC, and hippocampus volumes were unrelated to change in psychosocial variables (all p ≥ 0.44). However, individuals with larger baseline amygdalae experienced greater decreases in loneliness due to greater reductions in stress (0.35, p = 0.02). Further, individuals with larger baseline PFC volumes experienced greater reductions in stress due to greater increases in social support (-0.47, p = 0.02). No group differences in these pathways were observed. Conclusions: The social support environment and resulting reductions in stress, as opposed to exercise mode, may represent important features of exercise programs for improving older adults' perceived loneliness. As amygdala volume has been linked to anxiety, depression and impaired cognitive control processes in the PFC, moderation findings suggest further investigation in this area is warranted. Trial Registration: ClinicalTrials.gov identifier NCT01472744 (https://clinicaltrials.gov/ct2/show/NCT01472744?term=NCT01472744&rank=1).

Aerobic fitness is associated with greater hippocampal cerebral blood flow in children.

The present study is the first to investigate whether cerebral blood flow in the hippocampus relates to aerobic fitness in children. In particular, we used arterial spin labeling (ASL) perfusion MRI to provide a quantitative measure of blood flow in the hippocampus in 73 7- to 9-year-old preadolescent children. Indeed, aerobic fitness was found to relate to greater perfusion in the hippocampus, independent of age, sex, and hippocampal volume. Such results suggest improved microcirculation and cerebral vasculature in preadolescent children with higher levels of aerobic fitness. Further, aerobic fitness may influence how the brain regulates its metabolic demands via blood flow in a region of the brain important for learning and memory. To add specificity to the relationship of fitness to the hippocampus, we demonstrate no significant association between aerobic fitness and cerebral blood flow in the brainstem. Our results reinforce the importance of aerobic fitness during a critical period of child development.

White matter microstructure mediates the relationship between cardiorespiratory fitness and spatial working memory in older adults.

White matter structure declines with advancing age and has been associated with a decline in memory and executive processes in older adulthood. Yet, recent research suggests that higher physical activity and fitness levels may be associated with less white matter degeneration in late life, although the tract-specificity of this relationship is not well understood. In addition, these prior studies infrequently associate measures of white matter microstructure to cognitive outcomes, so the behavioral importance of higher levels of white matter microstructural organization with greater fitness levels remains a matter of speculation. Here we tested whether cardiorespiratory fitness (VO2max) levels were associated with white matter microstructure and whether this relationship constituted an indirect pathway between cardiorespiratory fitness and spatial working memory in two large, cognitively and neurologically healthy older adult samples. Diffusion tensor imaging was used to determine white matter microstructure in two separate groups: Experiment 1, N=113 (mean age=66.61) and Experiment 2, N=154 (mean age=65.66). Using a voxel-based regression approach, we found that higher VO2max was associated with higher fractional anisotropy (FA), a measure of white matter microstructure, in a diverse network of white matter tracts, including the anterior corona radiata, anterior internal capsule, fornix, cingulum, and corpus callosum (PFDR-corrected<.05). This effect was consistent across both samples even after controlling for age, gender, and education. Further, a statistical mediation analysis revealed that white matter microstructure within these regions, among others, constituted a significant indirect path between VO2max and spatial working memory performance. These results suggest that greater aerobic fitness levels are associated with higher levels of white matter microstructural organization, which may, in turn, preserve spatial memory performance in older adulthood.

Correction: The Role of Aerobic Fitness in Cortical Thickness and Mathematics Achievement in Preadolescent Children.

[This corrects the article DOI: 10.1371/journal.pone.0134115.].

Higher cardiorespiratory fitness levels are associated with greater hippocampal volume in breast cancer survivors.

As breast cancer treatment is associated with declines in brain and cognitive health, it is important to identify strategies to enhance the cognitive vitality of cancer survivors. In particular, the hippocampus is known to play an important role in brain and memory declines following cancer treatment. The hippocampus is also known for its plasticity and positive association with cardiorespiratory fitness (CRF). The present study explores whether CRF may hold promise for lessening declines in brain and cognitive health of a sample of breast cancer survivors within 3 years of completion of primary cancer treatment. We explored the role of cardiovascular fitness in hippocampal structure in breast cancer survivors and non-cancer female controls, as well as performed a median split to compare differences in hippocampal volume in relatively higher fit and lower fit cancer survivors and non-cancer controls. Indeed, CRF and total hippocampal volume were positively correlated in the cancer survivors. In particular, higher fit breast cancer survivors had comparable hippocampal volumes to non-cancer control participants (Cohen's d = 0.13; p > 0.3), whereas lower fit breast cancer survivors showed significantly smaller hippocampal volumes compared to both lower fit and higher fit control participants (Cohen's d = 0.87, p < 0.05). These results are the first to identify that CRF may protect the brain health of breast cancer survivors within 3 years of treatment. The present study uniquely contributes to the field of cancer and cognition and emphasizes the importance of investigating how individual differences in CRF play a role in brain changes of breast cancer survivors.

Brain activation during dual-task processing is associated with cardiorespiratory fitness and performance in older adults.

Higher cardiorespiratory fitness is associated with better cognitive performance and enhanced brain activation. Yet, the extent to which cardiorespiratory fitness-related brain activation is associated with better cognitive performance is not well understood. In this cross-sectional study, we examined whether the association between cardiorespiratory fitness and executive function was mediated by greater prefrontal cortex activation in healthy older adults. Brain activation was measured during dual-task performance with functional magnetic resonance imaging in a sample of 128 healthy older adults (59-80 years). Higher cardiorespiratory fitness was associated with greater activation during dual-task processing in several brain areas including the anterior cingulate and supplementary motor cortex (ACC/SMA), thalamus and basal ganglia, right motor/somatosensory cortex and middle frontal gyrus, and left somatosensory cortex, controlling for age, sex, education, and gray matter volume. Of these regions, greater ACC/SMA activation mediated the association between cardiorespiratory fitness and dual-task performance. We provide novel evidence that cardiorespiratory fitness may support cognitive performance by facilitating brain activation in a core region critical for executive function.