Age trajectories of functional activation under conditions of low and high processing demands: an adult lifespan fMRI study of the aging brain.

We examined functional activation across the adult lifespan in 316 healthy adults aged 20-89years on a judgment task that, across conditions, drew upon both semantic knowledge and ability to modulate neural function in response to cognitive challenge. Activation in core regions of the canonical semantic network (e.g., left IFG) were largely age-invariant, consistent with cognitive aging studies that show verbal knowledge is preserved across the lifespan. However, we observed a steady linear increase in activation with age in regions outside the core network, possibly as compensation to maintain function. Under conditions of increased task demands, we observed a stepwise reduction across the lifespan of modulation of activation to increasing task demands in cognitive control regions (frontal, parietal, anterior cingulate), paralleling the neural equivalent of "processing resources" described by cognitive aging theories. Middle-age was characterized by decreased modulation to task-demand in subcortical regions (caudate, nucleus accumbens, thalamus), and very old individuals showed reduced modulation to task difficulty in midbrain/brainstem regions (ventral tegmental, substantia nigra). These novel findings suggest that aging of activation to demand follows a gradient along the dopaminergic/nigrostriatal system, with earliest manifestation in fronto-parietal regions, followed by deficits in subcortical nuclei in middle-age and then to midbrain/brainstem dopaminergic regions in the very old.

The impact of sustained engagement on cognitive function in older adults: the Synapse Project.

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.

Age-related differences in memory-encoding fMRI responses after accounting for decline in vascular reactivity.

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 sides 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.

A comparison of physiologic modulators of fMRI signals.

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. Hum Brain Mapp 34:2078-2088, 2013. © 2011 Wiley Periodicals, Inc.

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.

An fMRI study of episodic encoding across the lifespan: changes in subsequent memory effects are evident by middle-age.

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.

Effects of beta-amyloid accumulation on neural function during encoding across the adult lifespan.

Limited functional imaging evidence suggests that 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 using (18)Florbetapir, 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.

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.

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.

Alterations in cerebral metabolic rate and blood supply across the adult lifespan.

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 (CMRO(2)), 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 CMRO(2) 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% CO(2) inhalation, was assessed and was reduced with age, the extent of which was more prominent than that of the resting state CBF.

Age-related neural dedifferentiation in the motor system.

Recent neuroimaging studies using multi-voxel pattern analysis (MVPA) show that distributed patterns of brain activation elicited by different visual stimuli are less distinctive in older adults than in young adults. However, less is known about the effects of aging on the neural representation of movement. The present study used MVPA to compare the distinctiveness of motor representations in young and older adults. We also investigated the contributions of brain structure to age differences in the distinctiveness of motor representations. We found that neural distinctiveness was reduced in older adults throughout the motor control network. Although aging was also associated with decreased gray matter volume in these regions, age differences in motor distinctiveness remained significant after controlling for gray matter volume. Our results suggest that age-related neural dedifferentiation is not restricted to sensory perception and is instead a more general feature of the aging brain.

Neural specificity predicts fluid processing ability in older adults.

We investigated whether individual differences in neural specificity-the distinctiveness of different neural representations-could explain individual differences in cognitive performance in older adults. Neural specificity was estimated based on how accurately multivariate pattern analysis identified neural activation patterns associated with specific experimental conditions. Neural specificity calculated from a same/different task on two categories of visual stimuli (faces and houses) significantly predicted performance on a range of fluid processing behavioral tasks (dot-comparison, digit-symbol, Trails-A, Trails-B, verbal-fluency) in older adults, whereas it did not correlate with a measure of crystallized knowledge (Shipley-vocabulary). In addition, the neural specificity measure accounted for 30% of the variance in a composite measure of fluid processing ability. These results are consistent with the hypothesis that loss of neural specificity, or dedifferentiation, contributes to reduced fluid processing ability in old age.

Culture differences in neural processing of faces and houses in the ventral visual cortex.

Behavioral and eye-tracking studies on cultural differences have found that while Westerners have a bias for analytic processing and attend more to face features, East Asians are more holistic and attend more to contextual scenes. In this neuroimaging study, we hypothesized that these culturally different visual processing styles would be associated with cultural differences in the selective activity of the fusiform regions for faces, and the parahippocampal and lingual regions for contextual stimuli. East Asians and Westerners passively viewed face and house stimuli during an functional magnetic resonance imaging experiment. As expected, we observed more selectivity for faces in Westerners in the left fusiform face area (FFA) reflecting a more analytic processing style. Additionally, Westerners showed bilateral activity to faces in the FFA whereas East Asians showed more right lateralization. In contrast, no cultural differences were detected in the parahippocampal place area (PPA), although there was a trend for East Asians to show greater house selectivity than Westerners in the lingual landmark area, consistent with more holistic processing in East Asians. These findings demonstrate group biases in Westerners and East Asians that operate on perceptual processing in the brain and are consistent with previous eye-tracking data that show cultural biases to faces.

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 x 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.

The impact of increased relational encoding demands on frontal and hippocampal function in older adults.

In the present study, we manipulated the cognitive effort in an associative encoding task using functional magnetic resonance imaging (fMRI). Older and younger adults were presented with two objects that were either semantically related or unrelated, and were required to form a relationship between the items. Both groups self-reported greater difficulty in completing the unrelated associative encoding task providing independent evidence of the associative difficulty manipulation. On both the low and high difficulty tasks, older adults showed a typical pattern of increased right inferior frontal recruitment relative to younger adults. Of particular interest was the finding that both groups showed increased activation as task difficulty increased in the left inferior frontal gyrus and left hippocampus. Overall, the results suggest that the aging brain is characterized by greater prefrontal processing, but that as cognitive demand increases, the networks used by older and younger adults are the largely the same.

Investigation and validation of intersite fMRI studies using the same imaging hardware.

PURPOSE: To provide a between-site comparison of functional MRI (fMRI) signal reproducibility in two laboratories equipped with identical imaging hardware and software. Many studies have looked at within-subject reliability and more recent efforts have begun to calibrate responses across sites, magnetic field strengths, and software. By comparing identical imaging hardware and software, we provide a benchmark for future multisite comparisons. MATERIALS AND METHODS: We evaluated system compatibility based on noise and stability properties of phantom scans and contrast estimates from repeated runs of a blocked motor and visual task on the same four subjects at both sites. RESULTS: Analysis of variance (ANOVA) and region of interest (ROI) analysis confirmed that site did not play a significant role in explaining variance in our large fMRI dataset. Effect size analysis shows that between-subject differences account for nearly 10 times more variance than site effects. CONCLUSION: We show that quantitative comparisons of contrast estimates derived from cognitive experiments can reliably be compared across two sites. This allows us to establish an effective platform for comparing group differences between two sites using fMRI when group effects are potentially confounded with site, as in the study of neurocultural differences between countries or multicenter clinical trials.

Age and culture modulate object processing and object-scene binding in the ventral visual area.

Behavioral differences in the visual processing of objects and backgrounds as a function of cultural group are well documented. Recent neuroimaging evidence also points to cultural differences in neural activation patterns. Compared with East Asians, Westerners' visual processing is more object focused, and they activate neural structures that reflect this bias for objects. In a recent adaptation study, East Asian older adults showed an absence of an object-processing area but normal adaptation for background areas. In the present study, 75 young and old adults (half East Asian and half Western) were tested in an fMR-adaptation study to examine differences in object and background processing as well as object-background binding. We found equivalent background processing in the parahippocampal gyrus in all four groups, diminished binding processes in the hippocampus in elderly East Asians and Westerners, and diminished object processing in elderly versus young adults in the lateral occipital complex. Moreover, elderly East Asians showed significantly less adaptation response in the object areas than did elderly Westerners. These findings demonstrate the malleability of perceptual processes as a result of differences in cohort-specific experiences or in cultural exposure over time.

Contextual interference in recognition memory with age.

Previous behavioral research suggests that although elderly adults' memory benefits from supportive context, misleading or irrelevant contexts produce greater interference. In the present study, we use event-related fMRI to investigate age differences when processing contextual information to make recognition judgments. Twenty-one young and twenty elderly incidentally encoded pictures of objects presented in meaningful contexts, and completed a memory test for the objects presented in identical or novel contexts. Elderly committed more false alarms than young when novel objects were presented in familiar, but task-irrelevant, contexts. Elderly showed reduced engagement of bilateral dorsolateral prefrontal cortex and anterior cingulate relative to young, reflecting disruption of a cognitive control network for processing context with age. Disruption occurred for both high and low-performing elderly, suggesting that cognitive control deficits are pervasive with age. Despite showing disruption of the cognitive control network, high-performing elderly recruited additional middle and medial frontal regions that were not recruited by either low-performing elderly or young adults. This suggests that high-performing elderly may compensate for the disruption of the cognitive control network by recruiting additional frontal resources to overcome cognitive control deficits that affect recognition memory.