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1.  The Impact of Sustained Engagement on Cognitive Function in Older Adults: The Synapse Project 
Psychological science  2013;25(1):103-112.
In the research reported here, we tested the hypothesis that sustained engagement in learning new skills that activated working memory, episodic memory, and reasoning over a period of 3 months would enhance cognitive function in older adults. In three conditions with high cognitive demands, participants learned to quilt, learned digital photography, or engaged in both activities for an average of 16.51 hr a week for 3 months. Results at posttest indicated that episodic memory was enhanced in these productive-engagement conditions relative to receptive-engagement conditions, in which participants either engaged in nonintellectual activities with a social group or performed low-demand cognitive tasks with no social contact. The findings suggest that sustained engagement in cognitively demanding, novel activities enhances memory function in older adulthood, but, somewhat surprisingly, we found limited cognitive benefits of sustained engagement in social activities.
doi:10.1177/0956797613499592
PMCID: PMC4154531  PMID: 24214244
cognitive aging; intervention; engagement; cognitive training; aging cognition; episodic memory; cognitive reserve; working memory
2.  Culture Wires the Brain: A Cognitive Neuroscience Perspective 
There is clear evidence that sustained experiences may affect both brain structure and function. Thus, it is quite reasonable to posit that sustained exposure to a set of cultural experiences and behavioral practices will affect neural structure and function. The burgeoning field of cultural psychology has often demonstrated the subtle differences in the way individuals process information—differences that appear to be a product of cultural experiences. We review evidence that the collectivistic and individualistic biases of East Asian and Western cultures, respectively, affect neural structure and function. We conclude that there is limited evidence that cultural experiences affect brain structure and considerably more evidence that neural function is affected by culture, particularly activations in ventral visual cortex—areas associated with perceptual processing.
doi:10.1177/1745691610374591
PMCID: PMC3409833  PMID: 22866061
fMRI; fMR-A; eye movement; cultural differences; ventral visual cortex; object; context; age
3.  Age-related differences in memory-encoding fMRI responses after accounting for decline in vascular reactivity 
NeuroImage  2013;78:415-425.
BOLD fMRI has provided a wealth of information about the aging brain. A common finding is that posterior regions of the brain manifest an age-related decrease in activation while the anterior regions show an age-related increase. Several neurocognitive models have been proposed to interpret these findings. However, one issue that has not been sufficiently considered to date is that the BOLD signal is based on vascular responses secondary to neural activity. Thus the above findings could be in part due to a vascular change, especially in view of the expected decline of vascular health with age. In the present study, we aim to examine age-related differences in memory-encoding fMRI response in the context of vascular aging. One hundred and thirty healthy subjects ranging from 20 to 89 years old underwent a scene-viewing fMRI task and, in the same session, cerebrovascular reactivity (CVR) was measured in each subject using a CO2-inhalation task. Without accounting for the influence of vascular changes, the task-activated fMRI signal showed the typical age-related decrease in visual cortex and medial temporal lobe (MTL), but manifested an increase in the right inferior frontal gyrus (IFG). In the same individuals, an age-related CVR reduction was observed in all of these regions. We then used a previously proposed normalization approach to calculate a CVR-corrected fMRI signal, which was defined as the uncorrected signal divided by CVR. Based on the CVR-corrected fMRI signal, an age-related increase is now seen in both the left and right side of IFG; and no brain regions showed a signal decrease with age. We additionally used a model-based approach to examine the fMRI data in the context of CVR, which again suggested an age-related change in the two frontal regions, but not in the visual and MTL regions.
doi:10.1016/j.neuroimage.2013.04.053
PMCID: PMC3694392  PMID: 23624491
cognitive aging; age-related increase; age-related decrease; cerebral vascular reactivity (CVR); functional magnetic resonance imaging (fMRI); fMRI normalization
4.  Parietal Functional Connectivity in Numerical Cognition 
Cerebral Cortex (New York, NY)  2012;23(9):2127-2135.
The parietal cortex is central to numerical cognition. The right parietal region is primarily involved in basic quantity processing, while the left parietal region is additionally involved in precise number processing and numerical operations. Little is known about how the 2 regions interact during numerical cognition. We hypothesized that functional connectivity between the right and left parietal cortex is critical for numerical processing that engages both basic number representation and learned numerical operations. To test this hypothesis, we estimated neural activity using functional magnetic resonance imaging in participants performing numerical and arithmetic processing on dot arrays. We first found task-based functional connectivity between a right parietal seed and the left sensorimotor cortex in all task conditions. As we hypothesized, we found enhanced functional connectivity between this right parietal seed and both the left parietal cortex and neighboring right parietal cortex, particularly during subtraction. The degree of functional connectivity also correlated with behavioral performance across individual participants, while activity within each region did not. These results highlight the role of parietal functional connectivity in numerical processing. They suggest that arithmetic processing depends on crosstalk between and within the parietal cortex and that this crosstalk contributes to one's numerical competence.
doi:10.1093/cercor/bhs193
PMCID: PMC3729197  PMID: 22784605
arithmetic processing; functional connectivity; intraparietal sulcus; numerical cognition
5.  How Does it STAC Up? Revisiting the Scaffolding Theory of Aging and Cognition 
Neuropsychology Review  2014;24(3):355-370.
“The Scaffolding Theory of Aging and Cognition (STAC)”, proposed in 2009, is a conceptual model of cognitive aging that integrated evidence from structural and functional neuroimaging to explain how the combined effects of adverse and compensatory neural processes produce varying levels of cognitive function. The model made clear and testable predictions about how different brain variables, both structural and functional, were related to cognitive function, focusing on the core construct of compensatory scaffolding. The present paper provides a revised model that integrates new evidence about the aging brain that has emerged since STAC was published 5 years ago. Unlike the original STAC model, STAC-r incorporates life-course factors that serve to enhance or deplete neural resources, thereby influencing the developmental course of brain structure and function, as well as cognition, over time. Life-course factors also influence compensatory processes that are engaged to meet cognitive challenge, and to ameliorate the adverse effects of structural and functional decline. The revised model is discussed in relation to recent lifespan and longitudinal data as well as emerging evidence about the effects of training interventions. STAC-r goes beyond the previous model by combining a life-span approach with a life-course approach to understand and predict cognitive status and rate of cognitive change over time.
doi:10.1007/s11065-014-9270-9
PMCID: PMC4150993  PMID: 25143069
Cognitive aging; Brain imaging; Scaffolding; Compensation
6.  Neural correlates of conceptual object priming in young and older adults: An event-related fMRI study 
Neurobiology of aging  2012;34(4):1254-1264.
In this event-related fMRI study, we investigated age-related differences in brain activity associated with conceptual repetition priming in young and older adults. Participants performed a speeded “living/non-living” classification task with three repetitions of familiar objects. Both young and older adults showed a similar magnitude of behavioral priming to repeated objects and evidencing repetition-related activation reductions in fusiform gyrus, superior occipital, middle and inferior temporal cortex, as well as inferior frontal and insula regions. The neural priming effect in young adults was extensive and continued through both the second and third stimulus repetitions, whereas neural priming in older adults was markedly attenuated and reached floor at the second repetition. In young adults, greater neural priming in multiple brain regions correlated with greater behavioral facilitation whereas in older adults, only activation reduction in the left inferior frontal correlated with faster behavioral responses. These findings provide evidence for altered neural priming in older adults despite preserved behavioral priming, and suggest the possibility that age-invariant behavioral priming is observed as a result of more sustained neural processing of stimuli in older adults which may be a form of compensatory neural activity.
doi:10.1016/j.neurobiolaging.2012.09.019
PMCID: PMC4028122  PMID: 23102512
Aging; fMRI; repetition priming; priming; implicit memory; recognition
7.  Risk Factors for β-Amyloid Deposition in Healthy Aging 
JAMA neurology  2013;70(5):600-606.
Importance
Identifying risk factors for increased β-amyloid (Aβ) deposition is important for targeting individuals most at risk for developing Alzheimer disease and informing clinical practice concerning prevention and early detection.
Objective
To investigate risk factors for Aβ deposition in cognitively healthy middle-aged and older adults. Specifically, we hypothesized that individuals with a vascular risk factor such as hypertension, in combination with a genetic risk factor for Alzheimer disease (apolipoprotein E ε4 allele), would show greater amyloid burden than those without such risk.
Design
Cross-sectional study.
Setting
General community.
Participants
One hundred eighteen well-screened and cognitively normal adults, aged 47 to 89 years. Participants were classified in the hypertension group if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic, as measured across 7 occasions at the time of study.
Intervention
Participants underwent Aβ positron emission tomography imaging with radiotracer fluorine 18–labeled florbetapir. Participants were genotyped for apolipoprotein E and were classified as ε4+ or ε4−.
Main Outcome Measure
Amyloid burden.
Results
Participants in the hypertension group with at least 1 ε4 allele showed significantly greater amyloid burden than those with only 1 risk factor or no risk factors. Furthermore, increased pulse pressure was strongly associated with increased mean cortical amyloid level for subjects with at least 1 ε4 allele.
Conclusions and Relevance
Vascular disease is a prevalent age-related condition that is highly responsive to both behavioral modification and medical treatment. Proper control and prevention of risk factors such as hypertension earlier in the life span may be one potential mechanism to ameliorate or delay neuropathological brain changes with aging.
doi:10.1001/jamaneurol.2013.1342
PMCID: PMC3968915  PMID: 23553344
8.  Age Differences in Default Mode Activity on Easy and Difficult Spatial Judgment Tasks 
The default network is a system of brain areas that are engaged when the mind is not involved in goal-directed activity. Most previous studies of age-related changes in default mode processing have used verbal tasks. We studied non-verbal spatial tasks that vary in difficulty. We presented old and young participants with two spatial judgment tasks: an easy categorical judgment and a more demanding coordinate judgment. We report that (a) Older adults show markedly less default network modulation than young on the demanding spatial task, but there is age equivalence on the easy task; (b) This Age × Task interaction is restricted to the default network: Brain areas that are deactivated by the tasks, but that are outside the default network, show no interaction; (c) Young adults exhibit significantly stronger functional connectivity among posterior regions of the default network compared with older adults, whereas older adults exhibit stronger connectivity between medial prefrontal cortex and other sites; and (d) The relationship of default activity to reaction time performance on the spatial tasks is mediated by age: in old adults, those who deactivate the default network most also perform best, whereas the opposite is true in younger adults. These results extend the findings of age-related changes in default mode processing and connectivity to visuo-spatial tasks and demonstrate that the results are specific to the default network.
doi:10.3389/neuro.09.075.2009
PMCID: PMC2814559  PMID: 20126437
default mode; deactivation; aging brain; spatial judgment; parietal cortex; connectivity; fMRI
9.  An fMRI study of episodic encoding across the lifespan: Changes in subsequent memory effects are evident by middle-age 
Neuropsychologia  2012;51(3):448-456.
Although it is well-documented that there are age differences between young and older adults in neural activity associated with successful memory formation (positive subsequent memory effects), little is known about how this activation differs across the lifespan, as few studies have included middle-aged adults. The present study investigated the effect of age on neural activity during episodic encoding using a cross-sectional lifespan sample (20–79 years old, N=192) from the Dallas Lifespan Brain Study. We report four major findings. First, in a contrast of remembered vs. forgotten items, a decrease in neural activity occurred with age in bilateral occipito-temporo-parietal regions. Second, when we contrasted forgotten with remembered items (negative subsequent memory), the primary difference was found between middle and older ages. Third, there was evidence for age equivalence in hippocampal regions, congruent with previous studies. Finally, low-memory-performers showed negative subsequent memory differences by middle age, whereas high memory performers did not demonstrate these differences until older age. Taken together, these findings delineate the importance of a lifespan approach to understanding neurocognitive aging and, in particular, the importance of a middle-age sample in revealing different trajectories.
doi:10.1016/j.neuropsychologia.2012.11.025
PMCID: PMC3563761  PMID: 23219676
aging; episodic memory; encoding; fMRI; lifespan; middle-age
10.  Culture-related differences in default network activity during visuo-spatial judgments 
Studies on culture-related differences in cognition have shown that Westerners attend more to object-related information, whereas East Asians attend more to contextual information. Neural correlates of these different culture-related visual processing styles have been reported in the ventral-visual and fronto-parietal regions. We conducted an fMRI study of East Asians and Westerners on a visuospatial judgment task that involved relative, contextual judgments, which are typically more challenging for Westerners. Participants judged the relative distances between a dot and a line in visual stimuli during task blocks and alternated finger presses during control blocks. Behaviorally, East Asians responded faster than Westerners, reflecting greater ease of the task for East Asians. In response to the greater task difficulty, Westerners showed greater neural engagement compared to East Asians in frontal, parietal, and occipital areas. Moreover, Westerners also showed greater suppression of the default network—a brain network that is suppressed under condition of high cognitive challenge. This study demonstrates for the first time that cultural differences in visual attention during a cognitive task are manifested both by differences in activation in fronto-parietal regions as well as suppression in default regions.
doi:10.1093/scan/nsr077
PMCID: PMC3575716  PMID: 22114080
culture; default network; fMRI; visuo-spatial processing
11.  Literacy, Cognitive Function, and Health: Results of the LitCog Study 
Journal of General Internal Medicine  2012;27(10):1300-1307.
ABSTRACT
BACKGROUND
Emerging evidence suggests the relationship between health literacy and health outcomes could be explained by cognitive abilities.
OBJECTIVE
To investigate to what degree cognitive skills explain associations between health literacy, performance on common health tasks, and functional health status.
DESIGN
Two face-to-face, structured interviews spaced a week apart with three health literacy assessments and a comprehensive cognitive battery measuring ‘fluid’ abilities necessary to learn and apply new information, and ‘crystallized’ abilities such as background knowledge.
SETTING
An academic general internal medicine practice and three federally qualified health centers in Chicago, Illinois.
PATIENTS
Eight hundred and eighty-two English-speaking adults ages 55 to 74.
MEASUREMENTS
Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine (REALM), Test of Functional Health Literacy in Adults (TOFHLA), and Newest Vital Sign (NVS). Performance on common health tasks were globally assessed and categorized as 1) comprehending print information, 2) recalling spoken information, 3) recalling multimedia information, 4) dosing and organizing medication, and 5) healthcare problem-solving.
RESULTS
Health literacy measures were strongly correlated with fluid and crystallized cognitive abilities (range: r = 0.57 to 0.77, all p < 0.001). Lower health literacy and weaker fluid and crystallized abilities were associated with poorer performance on healthcare tasks. In multivariable analyses, the association between health literacy and task performance was substantially reduced once fluid and crystallized cognitive abilities were entered into models (without cognitive abilities: β = −28.9, 95 % Confidence Interval (CI) -31.4 to −26.4, p; with cognitive abilities: β = −8.5, 95 % CI −10.9 to −6.0).
LIMITATIONS
Cross-sectional analyses, English-speaking, older adults only.
CONCLUSIONS
The most common measures used in health literacy studies are detecting individual differences in cognitive abilities, which may predict one’s capacity to engage in self-care and achieve desirable health outcomes. Future interventions should respond to all of the cognitive demands patients face in managing health, beyond reading and numeracy.
doi:10.1007/s11606-012-2079-4
PMCID: PMC3445686  PMID: 22566171
health literacy; cognitive abilities; health tasks; patient-reported outcomes; physical health; mental health
12.  A Comparison of Physiologic Modulators of fMRI Signals 
Human brain mapping  2012;34(9):2078-2088.
One of the main obstacles in quantitative interpretation of functional magnetic resonance imaging (fMRI) signal is that this signal is influenced by non-neural factors such as vascular properties of the brain, which effectively increases signal variability. One approach to account for non-neural components is to identify and measure these confounding factors and to include them as covariates in data analysis or interpretation. Previously, several research groups have independently identified four potential physiologic modulators of fMRI signals, including baseline venous oxygenation (Yv), cerebrovascular reactivity (CVR), resting state BOLD fluctuation amplitude (RSFA), and baseline cerebral blood flow (CBF). This study sought to directly compare the modulation effects of these indices in the same fMRI session. The physiologic parameters were measured with techniques comparable with those used in the previous studies except for CBF, which was determined globally with a velocity-based phase-contrast MRI (instead of arterial-spin-labeling MRI). Using an event-related, scene-categorization fMRI task, we showed that the fMRI signal amplitude was positively correlated with CVR (P < 0.0001) and RSFA (P = 0.002), while negatively correlated with baseline Yv (P < 0.0001). The fMRI-CBF correlation did not reach significance, although the (negative) sign of the correlation was consistent with the earlier study. Furthermore, among the physiologic modulators themselves, significant correlations were observed between baseline Yv and baseline CBF (P = 0.01), and between CVR and RSFA (P = 0.05), suggesting that some of the modulators may partly be of similar physiologic origins. These observations as well as findings in recent literature suggest that additional measurement of physiologic modulator(s) in an fMRI session may provide a practical approach to control for inter-subject variations and to improve the ability of fMRI in detecting disease or medication related differences.
doi:10.1002/hbm.22053
PMCID: PMC3432155  PMID: 22461234
BOLD fMRI; normalization; venous oxygenation; cerebrovascular reactivity; resting state BOLD fluctuation; cerebral blood flow
13.  Effects of Beta-Amyloid Accumulation on Neural Function During Encoding across the Adult Lifespan 
Neuroimage  2012;62(1):1-8.
Limited functional imaging evidence suggests increased beta-amyloid deposition is associated with alterations in brain function, even in healthy older adults. However, the majority of these findings report on resting-state activity or functional connectivity in adults over age 60. Much less is known about the impact of beta-amyloid on neural activations during cognitive task performance, or the impact of amyloid in young and middle-aged adults. The current study measured beta-amyloid burden from PET imaging using18Florbetapir, in a large continuous age sample of highly-screened, healthy adults (N = 137; aged 30–89 years). The same participants also underwent fMRI scanning, performing a memory encoding task. Using both beta-amyloid burden and age as continuous predictors of encoding activity, we report a dose-response relationship of beta-amyloid load to neural function, beyond the effects of age. Specifically, individuals with greater amyloid burden evidence less neural activation in bilateral dorsolateral prefrontal cortex, a region important for memory encoding, as well as reduced neural modulation in areas associated with default network activity: bilateral superior/medial frontal and lateral temporal cortex. Importantly, this reduction of both activation and suppression as a function of amyloid load was found across the lifespan, even in young- and middle-aged individuals. Moreover, this frontal and temporal amyloid-reduced activation/suppression was associated with poorer processing speed, verbal fluency, and fluid reasoning in a subgroup of individuals with elevated amyloid, suggesting that it is detrimental, rather than compensatory in nature.
doi:10.1016/j.neuroimage.2012.03.077
PMCID: PMC3381050  PMID: 22569063
14.  The aging mind: neuroplasticity in response to cognitive training 
Is it possible to enhance neural and cognitive function with cognitive training techniques? Can we delay age-related decline in cognitive function with interventions and stave off Alzheimer's disease? Does an aged brain really have the capacity to change in response to stimulation? In the present paper, we consider the neuroplasticity of the aging brain, that is, the brain's ability to increase capacity in response to sustained experience. We argue that, although there is some neural deterioration that occurs with age, the brain has the capacity to increase neural activity and develop neural scaffolding to regulate cognitive function. We suggest that increase in neural volume in response to cognitive training or experience is a clear indicator of change, but that changes in activation in response to cognitive training may be evidence of strategy change rather than indicative of neural plasticity. We note that the effect of cognitive training is surprisingly durable over time, but that the evidence that training effects transfer to other cognitive domains is relatively limited. We review evidence which suggests that engagement in an environment that requires sustained cognitive effort may facilitate cognitive function.
PMCID: PMC3622463  PMID: 23576894
neuroplasticity; scaffolding; cognitive training; cognitive reserve; engagement
15.  Sustained happiness? Lack of repetition suppression in right-ventral visual cortex for happy faces 
Emotional stimuli have been shown to preferentially engage initial attention but their sustained effects on neural processing remain largely unknown. The present study evaluated whether emotional faces engage sustained neural processing by examining the attenuation of neural repetition suppression to repeated emotional faces. Repetition suppression of neural function refers to the general reduction of neural activity when processing a repeated stimulus. Preferential processing of emotional face stimuli, however, should elicit sustained neural processing such that repetition suppression to repeated emotional faces is attenuated relative to faces with no emotional content. We measured the reduction of functional magnetic resonance imaging signals associated with immediate repetition of neutral, angry and happy faces. Whereas neutral faces elicited the greatest suppression in ventral visual cortex, followed by angry faces, repetition suppression was the most attenuated for happy faces. Indeed, happy faces showed almost no repetition suppression in part of the right-inferior occipital and fusiform gyri, which play an important role in face-identity processing. Our findings suggest that happy faces are associated with sustained visual encoding of face identity and thereby assist in the formation of more elaborate representations of the faces, congruent with findings in the behavioral literature.
doi:10.1093/scan/nsq058
PMCID: PMC3150853  PMID: 20584720
emotion; faces; repetition suppression; sustained processing; ventral visual cortex
16.  Alterations in Cerebral Metabolic Rate and Blood Supply across the Adult Lifespan 
Cerebral Cortex (New York, NY)  2010;21(6):1426-1434.
With age, the brain undergoes comprehensive changes in its function and physiology. Cerebral metabolism and blood supply are among the key physiologic processes supporting the daily function of the brain and may play an important role in age-related cognitive decline. Using MRI, it is now possible to make quantitative assessment of these parameters in a noninvasive manner. In the present study, we concurrently measured cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and venous blood oxygenation in a well-characterized healthy adult cohort from 20 to 89 years old (N = 232). Our data showed that CMRO2 increased significantly with age, while CBF decreased with age. This combination of higher demand and diminished supply resulted in a reduction of venous blood oxygenation with age. Regional CBF was also determined, and it was found that the spatial pattern of CBF decline was heterogeneous across the brain with prefrontal cortex, insular cortex, and caudate being the most affected regions. Aside from the resting state parameters, the blood vessels’ ability to dilate, measured by cerebrovascular reactivity to 5% CO2 inhalation, was assessed and was reduced with age, the extent of which was more prominent than that of the resting state CBF.
doi:10.1093/cercor/bhq224
PMCID: PMC3097991  PMID: 21051551
aging; blood oxygenation; cerebral blood flow; cerebral metabolism; cerebrovascular reactivity; MRI
17.  Neural Broadening or Neural Attenuation? Investigating Age-Related Dedifferentiation in the Face Network in a Large Lifespan Sample 
Previous studies have found that cortical responses to different stimuli become less distinctive as people get older. This age-related dedifferentiation may reflect the broadening of the tuning curves of category-selective neurons (broadening hypothesis) or it may be due to decreased activation of category-selective neurons (attenuation hypothesis). In this study, we evaluated these hypotheses in the context of the face-selective neural network. Over 300 participants, ranging in age from 20 to 89 years, viewed images of faces, houses, and control stimuli in a functional magnetic resonance imaging session. Regions within the core face network and extended face network were identified in individual subjects. Activation in many of these regions became significantly less face-selective with age, confirming previous reports of age-related dedifferentiation. Consistent with the broadening hypothesis, this dedifferentiation in the fusiform face area (FFA) was driven by increased activation to houses. In contrast, dedifferentiation in the extended face network was driven by decreased activation to faces, consistent with the attenuation hypothesis. These results suggest that age-related dedifferentiation reflects distinct processes in different brain areas. More specifically, dedifferentiation in FFA activity may be due to broadening of the tuning curves for face-selective neurons, while dedifferentiation in the extended face network reflects reduced face- or emotion-selective activity.
doi:10.1523/JNEUROSCI.4494-11.2012
PMCID: PMC3361757  PMID: 22323727
18.  The Adaptive Brain: Aging and Neurocognitive Scaffolding 
Annual Review of Psychology  2009;60:173-196.
There are declines with age in speed of processing, working memory, inhibitory function, and long-term memory, as well as decreases in brain structure size and white matter integrity. In the face of these decreases, functional imaging studies have demonstrated, somewhat surprisingly, reliable increases in prefrontal activation. To account for these joint phenomena, we propose the scaffolding theory of aging and cognition (STAC). STAC provides an integrative view of the aging mind, suggesting that pervasive increased frontal activation with age is a marker of an adaptive brain that engages in compensatory scaffolding in response to the challenges posed by declining neural structures and function. Scaffolding is a normal process present across the lifespan that involves use and development of complementary, alternative neural circuits to achieve a particular cognitive goal. Scaffolding is protective of cognitive function in the aging brain, and available evidence suggests that the ability to use this mechanism is strengthened by cognitive engagement, exercise, and low levels of default network engagement.
doi:10.1146/annurev.psych.59.103006.093656
PMCID: PMC3359129  PMID: 19035823
default network; dedifferentiation; hippocampus; compensation; cognitive reserve; frontal activation
19.  Neural Dissociation of Number from Letter Recognition and Its Relationship to Parietal Numerical Processing 
The visual recognition of letters dissociates from the recognition of numbers at both the behavioral and neural level. In this article, using fMRI, we investigate whether the visual recognition of numbers dissociates from letters, thereby establishing a double dissociation. In Experiment 1, participants viewed strings of consonants and Arabic numerals. We found that letters activated the left midfusiform and inferior temporal gyri more than numbers, replicating previous studies, whereas numbers activated a right lateral occipital area more than letters at the group level. Because the distinction between letters and numbers is culturally defined and relatively arbitrary, this double dissociation provides some of the strongest evidence to date that a neural dissociation can emerge as a result of experience. We then investigated a potential source of the observed neural dissociation. Specifically, we tested the hypothesis that lateralization of visual number recognition depends on lateralization of higher-order numerical processing. In Experiment 2, the same participants performed addition, subtraction, and counting on arrays of nonsymbolic stimuli varying in numerosity, which produced neural activity in and around the intraparietal sulcus, a region associated with higher-order numerical processing. We found that individual differences in the lateralization of number activity in visual cortex could be explained by individual differences in the lateralization of numerical processing in parietal cortex, suggesting a functional relationship between the two regions. Together, these results demonstrate a neural double dissociation between letter and number recognition and suggest that higher-level numerical processing in parietal cortex may influence the neural organization of number processing in visual cortex.
doi:10.1162/jocn_a_00085
PMCID: PMC3357212  PMID: 21736455
20.  Neuroplasticity and cognitive aging: The scaffolding theory of aging and cognition 
A recent proposal called the Scaffolding Theory of Cognitive Aging (STAC) postulates that functional changes with aging are part of a lifespan process of compensatory cognitive scaffolding that is an attempt to alleviate the cognitive declines associated with aging. Indeed, behavioral studies have shown that aging is associated with both decline as well as preservation of selective cognitive abilities. Similarly, neuroimaging studies have revealed selective changes in the aging brain that reflect neural decline as well as compensatory neural recruitment. While aging is associated with reductions in cortical thickness, white-matter integrity, dopaminergic activity, and functional engagement in posterior brain regions such as the hippocampus and occipital areas, there are compensatory increases in frontal functional engagement that correlate with better behavioral performance in older adults. In this review, we discuss these age-related behavioral and brain findings that support the STAC model of cognitive scaffolding and additionally integrate the findings on neuroplasticity as a compensatory response in the aging brain. As such, we also examine the impact of external experiences in facilitating neuroplasticity in older adults. Finally, having laid the foundation for STAC, we briefly describe a proposed intervention trial (The Synapse Program) designed to evaluate the behavioral and neural impact of engagement in lifestyle activities that facilitates successful cognitive scaffolding using a controlled experiment where older adult participants are randomly assigned to different conditions of engagement.
doi:10.3233/RNN-2009-0493
PMCID: PMC3355626  PMID: 19847066
21.  Both left and right posterior parietal activations contribute to compensatory processes in normal aging 
Neuropsychologia  2011;50(1):55-66.
Older adults often exhibit greater brain activation in prefrontal cortex compared to younger adults, and there is some evidence that this increased activation compensates for age-related neural degradation that would otherwise adversely affect cognitive performance. Less is known about aging and compensatory recruitment in the parietal cortex. In this event-related functional magnetic resonance imaging study, we presented healthy young and old participants with two Stroop-like tasks (number magnitude and physical size). In young, the number magnitude task activated right parietal cortex and the physical size task activated left parietal cortex. In older adults, we observed contralateral parietal recruitment that depended on the task: in the number magnitude task older participants recruited left posterior parietal cortex (in addition to the right parietal activity observed in young) while in the physical size task they recruited right (in addition to left) posterior parietal cortex. In both cases, the additional parietal activity was associated with better performance suggesting that it played a compensatory role. Older adults also recruited left prefrontal cortex during both tasks and this common activation was also associated with better performance. The results provide evidence for task-specific compensatory recruitment in parietal cortex as well as task-independent compensatory recruitment in prefrontal cortex in normal aging.
doi:10.1016/j.neuropsychologia.2011.10.022
PMCID: PMC3355662  PMID: 22063904
Age-related compensation; Event-related fMRI; Interference resolution; Posterior parietal cortex; Prefrontal cortex
22.  Age differences in neural distinctiveness revealed by multi-voxel pattern analysis 
NeuroImage  2010;56(2):736-743.
Current theories of cognitive aging argue that neural representations become less distinctive in old age, a phenomenon known as dedifferentiation. The present study used multi-voxel pattern analysis (MVPA) to measure age differences in the distinctiveness of distributed patterns of neural activation evoked by different categories of visual images. We found that neural activation patterns within the ventral visual cortex were less distinctive among older adults. Further, we report that age differences in neural distinctiveness extend beyond the ventral visual cortex: older adults also showed decreased distinctiveness in early visual cortex, inferior parietal cortex, and medial and lateral prefrontal cortex. Neural distinctiveness scores in early and late visual areas were highly correlated, suggesting shared mechanisms of age-related decline. Finally, we investigated whether older adults can compensate for altered processing in visual cortex by encoding stimulus information across larger numbers of voxels within the visual cortex or in regions outside visual cortex. We found no evidence that older adults can increase the distinctiveness of distributed activation patterns, either within or beyond the visual cortex. Our results have important implications for theories of cognitive aging and highlight the value of MVPA to the study of neural coding in the aging brain.
doi:10.1016/j.neuroimage.2010.04.267
PMCID: PMC2962693  PMID: 20451629
aging; fMRI; MVPA; dedifferentiation; compensation; ventral visual cortex
23.  Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease 
The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.
doi:10.1016/j.jalz.2011.03.003
PMCID: PMC3220946  PMID: 21514248
Preclinical Alzheimer's disease; Biomarker; Amyloid; Neurodegeneration; Prevention
24.  A framework on surface-based connectivity quantification for the human brain 
Journal of neuroscience methods  2011;197(2):324-332.
Quantifying the connectivity between arbitrary surface patches in the human brain cortex can be used in studies on brain function and to characterize clinical diseases involving abnormal connectivity. Cortical regions of human brain in their natural forms can be represented in surface formats. In this paper, we present a framework to quantify connectivity using cortical surface segmentation and labeling from structural magnetic resonance images, tractography from diffusion tensor images, and nonlinear inter-subject registration. For a single subject, the connectivity intensity of any point on the cortical surface is set to unity if the point is connected and zero if it is not connected. The connectivity proportion is defined as the ratio of the total connected surface area to the total area of the surface patch. By nonlinearly registering the connectivity data of a group of normal controls into a template space, a population connectivity metric can be defined as either the average connectivity intensity of a cortical point or the average connectivity proportion of a cortical region. In the template space, a connectivity profile and a connectivity histogram of an arbitrary cortical region of interest can then be derived from these connectivity quantification values. Results from the application of these quantification metrics to a population of schizophrenia patients and normal controls are presented, revealing connectivity signatures of specified cortical regions and detecting connectivity abnormalities.
doi:10.1016/j.jneumeth.2011.02.017
PMCID: PMC3081907  PMID: 21396960
connectivity; quantification; DTI; cortical surface; tractography
25.  Investigating Unique Environmental Contributions to the Neural Representation of Written Words: A Monozygotic Twin Study 
PLoS ONE  2012;7(2):e31512.
The visual word form area (VWFA) is a region of left inferior occipitotemporal cortex that is critically involved in visual word recognition. Previous studies have investigated whether and how experience shapes the functional characteristics of VWFA by comparing neural response magnitude in response to words and nonwords. Conflicting results have been obtained, however, perhaps because response magnitude can be influenced by other factors such as attention. In this study, we measured neural activity in monozygotic twins, using functional magnetic resonance imaging. This allowed us to quantify differences in unique environmental contributions to neural activation evoked by words, pseudowords, consonant strings, and false fonts in the VWFA and striate cortex. The results demonstrate significantly greater effects of unique environment in the word and pseudoword conditions compared to the consonant string and false font conditions both in VWFA and in left striate cortex. These findings provide direct evidence for environmental contributions to the neural architecture for reading, and suggest that learning phonology and/or orthographic patterns plays the biggest role in shaping that architecture.
doi:10.1371/journal.pone.0031512
PMCID: PMC3275550  PMID: 22347490

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