Edge-Community Entropy Is a Novel Neural Correlate of Aging and Moderator of Fluid Cognition.

Decreased neuronal specificity of the brain in response to cognitive demands (i.e., neural dedifferentiation) has been implicated in age-related cognitive decline. Investigations into functional connectivity analogs of these processes have focused primarily on measuring segregation of nonoverlapping networks at rest. Here, we used an edge-centric network approach to derive entropy, a measure of specialization, from spatially overlapping communities during cognitive task fMRI. Using Human Connectome Project Lifespan data (713 participants, 36-100 years old, 55.7% female), we characterized a pattern of nodal despecialization differentially affecting the medial temporal lobe and limbic, visual, and subcortical systems. At the whole-brain level, global entropy moderated declines in fluid cognition across the lifespan and uniquely covaried with age when controlling for the network segregation metric modularity. Importantly, relationships between both metrics (entropy and modularity) and fluid cognition were age dependent, although entropy's relationship with cognition was specific to older adults. These results suggest entropy is a potentially important metric for examining how neurological processes in aging affect functional specialization at the nodal, network, and whole-brain level.

The influence of aerobic fitness on cerebral white matter integrity and cognitive function in older adults: results of a one-year exercise intervention.

Cerebral white matter (WM) degeneration occurs with increasing age and is associated with declining cognitive function. Research has shown that cardiorespiratory fitness and exercise are effective as protective, even restorative, agents against cognitive and neurobiological impairments in older adults. In this study, we investigated whether the beneficial impact of aerobic fitness would extend to WM integrity in the context of a one-year exercise intervention. Further, we examined the pattern of diffusivity changes to better understand the underlying biological mechanisms. Finally, we assessed whether training-induced changes in WM integrity would be associated with improvements in cognitive performance independent of aerobic fitness gains. Results showed that aerobic fitness training did not affect group-level change in WM integrity, executive function, or short-term memory, but that greater aerobic fitness derived from the walking program was associated with greater change in WM integrity in the frontal and temporal lobes, and greater improvement in short-term memory. Increases in WM integrity, however, were not associated with short-term memory improvement, independent of fitness improvements. Therefore, while not all findings are consistent with previous research, we provide novel evidence for correlated change in training-induced aerobic fitness, WM integrity, and cognition among healthy older adults.

Using connectome-based models of working memory to predict emotion regulation in older adults.

Older adulthood is characterized by enhanced emotional well-being potentially resulting from greater reliance on adaptive emotion regulation strategies. However, not all older adults demonstrate an increase in emotional well-being and instead rely on maladaptive emotion regulation strategies. An important moderator of age-related shifts in strategy preferences is working memory (WM) and its underlying neural circuitry. As such, individual differences in the neural integrity underlying WM may predict older adults' emotion regulation strategy preferences. Our study used whole-brain WM networks-derived from young adults using connectome-based predictive modeling-to predict WM performance and acceptance strategy use in healthy older adults. Older adults (N = 110) completed baseline assessments as part of a randomized controlled trial examining the impact of mind-body interventions on healthy aging. Our results revealed that the WM networks predicted WM accuracy but not acceptance use or difficulties in emotion regulation in older adults. Individual differences in WM performance, but not WM networks, moderated relationships between image intensity and acceptance use. These findings highlight that robust neural markers of WM generalize to an independent sample of healthy older adults but may not generalize beyond cognitive domains to predict emotion-based behaviors.

Understanding the health effects of caregiving stress: New directions in molecular aging.

Dementia caregiving has been linked to multiple health risks, including infectious illness, depression, anxiety, immune dysregulation, weakened vaccine responses, slow wound healing, hypertension, cardiovascular disease, metabolic syndrome, diabetes, frailty, cognitive decline, and reduced structural and functional integrity of the brain. The sustained overproduction of proinflammatory cytokines is a key pathway behind many of these risks. However, contrasting findings suggest that some forms of caregiving may have beneficial effects, such as maintaining caregivers' health and providing a sense of meaning and purpose which, in turn, may contribute to lower rates of functional decline and mortality. The current review synthesizes these disparate literatures, identifies methodological sources of discrepancy, and integrates caregiver research with work on aging biomarkers to propose a research agenda that traces the mechanistic pathways of caregivers' health trajectories with a focus on the unique stressors facing spousal caregivers as compared to other informal caregivers. Combined with a focus on psychosocial moderators and mechanisms, studies using state-of-the-art molecular aging biomarkers such as telomere length, p16INK4a, and epigenetic age could help to reconcile mixed literature on caregiving's sequelae by determining whether and under what conditions caregiving-related experiences contribute to faster aging, in part through inflammatory biology. The biomarkers predict morbidity and mortality, and each contributes non-redundant information about age-related molecular changes -together painting a more complete picture of biological aging. Indeed, assessing changes in these biopsychosocial mechanisms over time would help to clarify the dynamic relationships between caregiving experiences, psychological states, immune function, and aging.

Trait mindfulness and emotion regulation responsiveness to negative affect in daily life.

Objectives: Recent conceptualizations of adaptive emotion regulation is predicated on the ability to flexibly use emotion regulation strategies to meet changing contextual demands. Although trait mindfulness has been linked to enhanced emotional well-being and use of adaptive emotion regulation strategies, there is a dearth of literature examining associations between trait mindfulness and emotion regulation flexibility. Further, despite a rich literature suggesting that emotion regulation processes change with age, no study to date has assessed whether the role of trait mindfulness on emotion regulation responsiveness to negative emotions-a component of emotion regulation flexibility-differs between young and older adults. Methods: The current study recruited 130 young adults and 130 older adults to assess trait mindfulness, emotion regulation strategy use, and emotion regulation responsiveness of six distinct strategies in daily life. Results: Across the full sample, trait mindfulness was related to reduced distraction (ß = -0.11, t(238.09) = -3.02, p = .003) and expressive suppression (ß = -0.15, t(237.70) = -4.62, p < .001) strategy use. Age moderation analyses revealed that trait mindfulness was associated with reduced expressive suppression responsiveness (ß = 0.12, t(247) = 2.31, p = .022) in young adults and increased detached reappraisal responsiveness among older adults (ß = 0.15, t(247) = -2.95, p = .003). Conclusions: The current findings highlight the importance of understanding how trait mindfulness is associated with strategy use and responsiveness to negative affect changes in daily life as well as how these patterns may shift across the lifespan. Manuscript Pre-registration: Open Science Framework, registration number: z5g8v.

Functional connectivity patterns are altered by low back pain and cause different responses to sham and real dry needling therapies: a systematic review of fMRI studies.

BACKGROUND: There is a relationship between low back pain (LBP) and central nervous system dysfunction. Needling therapies (e.g. acupuncture, dry needling) are proposed to impact the nervous system, however their specific influence is unclear. PURPOSE: Determine how needling therapies alter functional connectivity and LBP as measured by functional magnetic resonance imaging (fMRI). METHODS: Databases were searched following PRISMA guidelines. Studies using fMRI on individuals with LBP receiving dry needling or acupuncture compared to control or sham treatments were included. RESULTS: Eight studies were included, all of which used acupuncture. The quality of studies ranged from good (n = 6) to excellent (n = 2). After acupuncture, individuals with LBP demonstrated significant functional connectivity changes across several networks, notably the salience, somatomotor, default mode network (DMN) and limbic networks. A meta-analysis demonstrated evidence of no effect to potential small effect of acupuncture in reducing LBP (SMD -0.28; 95% CI: -0.70, 0.13). CONCLUSION: Needling therapies, like acupuncture, may have a central effect on patients beyond the local tissue effects, reducing patients' pain and disability due to alterations in neural processing, including the DMN, and potentially other central nervous system effects. The meta-analysis should be interpreted with caution due to the narrow focus and confined sample used.

TRACking health behaviors in people with Multiple Sclerosis (TRAC-MS): Study protocol and description of the study sample.

Introduction: People with multiple sclerosis (PwMS) experience a range of physical, cognitive, and affective symptoms. Behavioral interventions targeting increased physical activity show promising support as low-cost methods to improve working memory, episodic memory, and processing speed in PwMS. In this randomized controlled trial, we will examine the efficacy of a pedometer-tracking intervention, designed to increase low-to-moderate levels of physical activity, for improving working memory in PwMS. Methods and Analysis: Eighty-seven PwMS, between the ages of 30-59, have been recruited for the study. Seventy-five of the eligible and interested individuals were randomized to six-month health behavior monitoring groups: a Step-track group or a Water-track group (serving as the active control). Neuropsychological measures, assessing the primary outcome of the study, were administered at pre, midpoint, and post-intervention. Exploratory factor analysis of neuropsychological measures resulted in three factors: a working memory/processing speed factor, a visual episodic memory factor, and a verbal episodic memory factor. Changes in this latent measure of working memory/processing speed is the primary outcome of the current study. Functional MRI data will be analyzed to examine changes in the functional connectivity of the neural network supporting working memory. Ethics and dissemination: The institutional review board granted approval for the study and all participants provided written informed consent. The results of this study will provide support showing that step-tracking increases overall levels of physical activity, improves working memory and processing speed, and strengthens the neural circuitry that supports better cognition. Evidence from this study will thus offer promising support for the routine use of step-tracking devices to improve cognitive functioning in PwMS. Study results will be disseminated through peer-reviewed publications and presentations at scientific conferences.

Striatal volume predicts level of video game skill acquisition.

Video game skills transfer to other tasks, but individual differences in performance and in learning and transfer rates make it difficult to identify the source of transfer benefits. We asked whether variability in initial acquisition and of improvement in performance on a demanding video game, the Space Fortress game, could be predicted by variations in the pretraining volume of either of 2 key brain regions implicated in learning and memory: the striatum, implicated in procedural learning and cognitive flexibility, and the hippocampus, implicated in declarative memory. We found that hippocampal volumes did not predict learning improvement but that striatal volumes did. Moreover, for the striatum, the volumes of the dorsal striatum predicted improvement in performance but the volumes of the ventral striatum did not. Both ventral and dorsal striatal volumes predicted early acquisition rates. Furthermore, this early-stage correlation between striatal volumes and learning held regardless of the cognitive flexibility demands of the game versions, whereas the predictive power of the dorsal striatal volumes held selectively for performance improvements in a game version emphasizing cognitive flexibility. These findings suggest a neuroanatomical basis for the superiority of training strategies that promote cognitive flexibility and transfer to untrained tasks.

Aerobic fitness is associated with hippocampal volume in elderly humans.

Deterioration of the hippocampus occurs in elderly individuals with and without dementia, yet individual variation exists in the degree and rate of hippocampal decay. Determining the factors that influence individual variation in the magnitude and rate of hippocampal decay may help promote lifestyle changes that prevent such deterioration from taking place. Aerobic fitness and exercise are effective at preventing cortical decay and cognitive impairment in older adults and epidemiological studies suggest that physical activity can reduce the risk for developing dementia. However, the relationship between aerobic fitness and hippocampal volume in elderly humans is unknown. In this study, we investigated whether individuals with higher levels of aerobic fitness displayed greater volume of the hippocampus and better spatial memory performance than individuals with lower fitness levels. Furthermore, in exploratory analyses, we assessed whether hippocampal volume mediated the relationship between fitness and spatial memory. Using a region-of-interest analysis on magnetic resonance images in 165 nondemented older adults, we found a triple association such that higher fitness levels were associated with larger left and right hippocampi after controlling for age, sex, and years of education, and larger hippocampi and higher fitness levels were correlated with better spatial memory performance. Furthermore, we demonstrated that hippocampal volume partially mediated the relationship between higher fitness levels and enhanced spatial memory. Our results clearly indicate that higher levels of aerobic fitness are associated with increased hippocampal volume in older humans, which translates to better memory function.

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.

BDNF mediates improvements in executive function following a 1-year exercise intervention.

Executive function declines with age, but engaging in aerobic exercise may attenuate decline. One mechanism by which aerobic exercise may preserve executive function is through the up-regulation of brain-derived neurotropic factor (BDNF), which also declines with age. The present study examined BDNF as a mediator of the effects of a 1-year walking intervention on executive function in 90 older adults (mean age = 66.82). Participants were randomized to a stretching and toning control group or a moderate intensity walking intervention group. BDNF serum levels and performance on a task-switching paradigm were collected at baseline and follow-up. We found that age moderated the effect of intervention group on changes in BDNF levels, with those in the highest age quartile showing the greatest increase in BDNF after 1-year of moderate intensity walking exercise (p = 0.036). The mediation analyses revealed that BDNF mediated the effect of the intervention on task-switch accuracy, but did so as a function of age, such that exercise-induced changes in BDNF mediated the effect of exercise on task-switch performance only for individuals over the age of 71. These results demonstrate that both age and BDNF serum levels are important factors to consider when investigating the mechanisms by which exercise interventions influence cognitive outcomes, particularly in elderly populations.

Examining neural correlates of skill acquisition in a complex videogame training program.

Acquisition of complex skills is a universal feature of human behavior that has been conceptualized as a process that starts with intense resource dependency, requires effortful cognitive control, and ends in relative automaticity on the multi-faceted task. The present study examined the effects of different theoretically based training strategies on cortical recruitment during acquisition of complex video game skills. Seventy-five participants were recruited and assigned to one of three training groups: (1) Fixed Emphasis Training (FET), in which participants practiced the game, (2) Hybrid Variable-Priority Training (HVT), in which participants practiced using a combination of part-task training and variable priority training, or (3) a Control group that received limited game play. After 30 h of training, game data indicated a significant advantage for the two training groups relative to the control group. The HVT group demonstrated enhanced benefits of training, as indexed by an improvement in overall game score and a reduction in cortical recruitment post-training. Specifically, while both groups demonstrated a significant reduction of activation in attentional control areas, namely the right middle frontal gyrus, right superior frontal gyrus, and the ventral medial prefrontal cortex, participants in the control group continued to engage these areas post-training, suggesting a sustained reliance on attentional regions during challenging task demands. The HVT group showed a further reduction in neural resources post-training compared to the FET group in these cognitive control regions, along with reduced activation in the motor and sensory cortices and the posteromedial cortex. Findings suggest that training, specifically one that emphasizes cognitive flexibility can reduce the attentional demands of a complex cognitive task, along with reduced reliance on the motor network.

Predicting individuals' learning success from patterns of pre-learning MRI activity.

Performance in most complex cognitive and psychomotor tasks improves with training, yet the extent of improvement varies among individuals. Is it possible to forecast the benefit that a person might reap from training? Several behavioral measures have been used to predict individual differences in task improvement, but their predictive power is limited. Here we show that individual differences in patterns of time-averaged T2*-weighted MRI images in the dorsal striatum recorded at the initial stage of training predict subsequent learning success in a complex video game with high accuracy. These predictions explained more than half of the variance in learning success among individuals, suggesting that individual differences in neuroanatomy or persistent physiology predict whether and to what extent people will benefit from training in a complex task. Surprisingly, predictions from white matter were highly accurate, while voxels in the gray matter of the dorsal striatum did not contain any information about future training success. Prediction accuracy was higher in the anterior than the posterior half of the dorsal striatum. The link between trainability and the time-averaged T2*-weighted signal in the dorsal striatum reaffirms the role of this part of the basal ganglia in learning and executive functions, such as task-switching and task coordination processes. The ability to predict who will benefit from training by using neuroimaging data collected in the early training phase may have far-reaching implications for the assessment of candidates for specific training programs as well as the study of populations that show deficiencies in learning new skills.

Cardiorespiratory fitness, hippocampal volume, and frequency of forgetting in older adults.

OBJECTIVE: The purpose of this study was to extend our earlier work to determine the extent to which cardiorespiratory fitness is associated with the frequency of memory problems via its effects on the hippocampus and spatial working memory. We hypothesized that age, sex, education, body composition, and physical activity were direct determinants of fitness, which, in turn, influenced frequency of forgetting indirectly through hippocampal volume and spatial working memory. METHOD: We conducted assessments of demographic characteristics, Body Mass Index (BMI), physical activity, cardiorespiratory fitness, hippocampal volume, spatial working memory, and frequency of forgetting in 158 older adults (M age = 66.49). Path analyses within a covariance modeling framework were used to examine relationships among these constructs. RESULTS: Sex, age, BMI, and education were all significant determinants of cardiorespiratory fitness. The hypothesized path models for testing the effects of fitness on frequency of forgetting through hippocampal volume and accuracy and speed of spatial working memory all fit the data well. CONCLUSIONS: Our findings suggest that older adults with higher levels of fitness show greater preservation of hippocampal volume, which, in turn, is associated with more accurate and faster spatial memory and fewer episodes of forgetting. Given the proportion of older adults reporting memory problems, it is necessary to determine whether improvements in fitness brought about by physical activity interventions can result in subsequent attenuation of memory problems or potentially in improvements in memory.

A cross-sectional study of hormone treatment and hippocampal volume in postmenopausal women: evidence for a limited window of opportunity.

The influence of hormone treatment on brain and cognition in postmenopausal women has been a controversial topic. Contradictory patterns of results have prompted speculation that a critical period, or limited window of opportunity, exists for hormone treatment to protect against neurocognitive. In this cross-sectional study of 102 postmenopausal women, we examined whether hippocampal, amygdala, or caudate nucleus volumes and spatial memory performance were related to the interval between menopause and the initiation of hormone treatment. Consistent with a critical period hypothesis, we found that shorter intervals between menopause and the initiation of hormone treatment were associated with larger hippocampal volumes compared with longer intervals between menopause and treatment initiation. Initiation of hormone treatment at the time of menopause was also associated with larger hippocampal volumes when compared with peers who had never used hormone treatment. Furthermore, these effects were independent from potentially confounding factors such as age, years of education, the duration of hormone treatment, current or past use of hormone therapy, the type of therapy, and age at menopause. Larger hippocampal volumes in women who initiated hormone treatment at the time of menopause failed to translate to improved spatial memory performance. There was no relationship between timing of hormone initiation, spatial memory performance, and amygdala or caudate nucleus volume. Our results provide support for a limited window of opportunity for hormone treatment to influence hippocampal volume, yet the degree to which these effects translate to improved memory performance is uncertain.

Plasticity of brain networks in a randomized intervention trial of exercise training in older adults.

Research has shown the human brain is organized into separable functional networks during rest and varied states of cognition, and that aging is associated with specific network dysfunctions. The present study used functional magnetic resonance imaging (fMRI) to examine low-frequency (0.008 < f < 0.08 Hz) coherence of cognitively relevant and sensory brain networks in older adults who participated in a 1-year intervention trial, comparing the effects of aerobic and non-aerobic fitness training on brain function and cognition. Results showed that aerobic training improved the aging brain's resting functional efficiency in higher-level cognitive networks. One year of walking increased functional connectivity between aspects of the frontal, posterior, and temporal cortices within the Default Mode Network and a Frontal Executive Network, two brain networks central to brain dysfunction in aging. Length of training was also an important factor. Effects in favor of the walking group were observed only after 12 months of training, compared to non-significant trends after 6 months. A non-aerobic stretching and toning group also showed increased functional connectivity in the DMN after 6 months and in a Frontal Parietal Network after 12 months, possibly reflecting experience-dependent plasticity. Finally, we found that changes in functional connectivity were behaviorally relevant. Increased functional connectivity was associated with greater improvement in executive function. Therefore the study provides the first evidence for exercise-induced functional plasticity in large-scale brain systems in the aging brain, using functional connectivity techniques, and offers new insight into the role of aerobic fitness in attenuating age-related brain dysfunction.

Functional connectivity: a source of variance in the association between cardiorespiratory fitness and cognition?

Over the next 20 years the number of Americans diagnosed with dementia is expected to more than double (CDC, 2007). It is, therefore, an important public health initiative to understand what factors contribute to the longevity of a healthy mind. Both default mode network (DMN) function and increased aerobic fitness have been associated with better cognitive performance and reduced incidence of Alzheimer's disease among older adults. Here we examine the association between aerobic fitness, functional connectivity in the DMN, and cognitive performance. Results showed significant age-related deficits in functional connectivity in both local and distributed DMN pathways. However, in a group of healthy elderly adults, almost half of the age-related disconnections showed increased functional connectivity as a function of aerobic fitness level. Finally, we examine the hypothesis that functional connectivity in the DMN is one source of variance in the relationship between aerobic fitness and cognition. Results demonstrate instances of both specific and global DMN connectivity mediating the relationship between fitness and cognition. We provide the first evidence for functional connectivity as a source of variance in the association between aerobic fitness and cognition, and discuss results in the context of neurobiological theories of cognitive aging and disease.

Dedifferentiation in the visual cortex: an fMRI investigation of individual differences in older adults.

Dedifferentiation, or decreased processing specificity, has been suggested to represent a ubiquitous characteristic of cognitive aging. In this study, we examined both age-related differences and intra-group differences in neural specificity in the ventral visual cortex for color, words, faces and places. Our results demonstrated that neural dedifferentiation was not ubiquitous across stimulus categories. Neural dedifferentiation was also relatively stable, across age, in a group of older adults. Older adults with more overall gray matter showed less neural dedifferentiation in the visual cortex. However, regional gray matter volume was not associated with neural dedifferentiation. We illustrate these effects using a discriminability metric, a signal detection theory measure, for neural dedifferentiation that takes into account both magnitude and variance of brain activation. The dedifferentiation measure provides a quantitative means to examine activation patterns and individual difference factors associated with neural dedifferentiation, and to test theories of behavioral dedifferentiation in cognitive aging literature.