Relating medial temporal lobe volume to frontal fMRI activation for memory encoding in older adults

Neuroimaging research on the brain basis of memory decline in older adults typically has examined age-related changes either in structure or in function. Structural imaging studies have found that smaller medial temporal lobe (MTL) volumes are associated with lower memory performance. Functional imaging studies have found that older adults often exhibit bilateral frontal-lobe activation under conditions where young adults exhibit unilateral frontal activation. As yet, no one has examined whether these MTL structural and frontal-lobe functional findings are associated. In this study, we tested whether these findings were correlated in a population of healthy older adults in whom we previously demonstrated verbal memory performance was positively associated with left entorhinal cortex volume in the MTL (Rosen et al., 2003) and right frontal lobe activation during memory encoding (Rosen et al., 2002). Thirteen, non-demented, community-dwelling older adults participated both in a functional MRI (fMRI) study of verbal memory encoding and structural imaging. MRI-derived left entorhinal volume was measured on structural images and entered as a regressor against fMRI activation during verbal memory encoding. Right frontal activation (Brodmann's Area 47/insula) was positively correlated with left entorhinal cortex volume. These findings indicate a positive association between MTL volume and right frontal-lobe function that may underlie variability in memory performance among the elderly, and also suggest a two-stage model of memory decline in aging.     

Hemispheric asymmetry and aging: right hemisphere decline or asymmetry reduction

We review evidence for two models of hemispheric asymmetry and aging: the right hemi-aging model, which proposes that the right hemisphere shows greater age-related decline than the left hemisphere, and the hemispheric asymmetry reduction in old adults (HAROLD) model, which proposes that frontal activity during cognitive performance tends to be less lateralized in older than in younger adults. The right hemi-aging model is supported by behavioral studies in the domains of cognitive, affective, and sensorimotor processing, but the evidence has been mixed. In contrast, available evidence is generally consistent with the HAROLD model, which is supported primarily by functional neuroimaging evidence in the domains of episodic memory encoding and retrieval, semantic memory retrieval, working memory, perception, and inhibitory control. Age-related asymmetry reductions may reflect functional compensation or dedifferentiation, and the evidence, although scarce, tends to support the compensation hypothesis. The right hemi-aging and the HAROLD models are not incompatible. For example, the latter may apply to prefrontal regions and the former to other brain regions.     

An fMRI study of the functional neuroanatomy of picture encoding in younger and older adults

Age-related changes in the neural mechanisms of picture encoding were investigated using functional magnetic resonance imaging (fMRI). Seven younger and seven older adults were studied while they were encoding pairs of concrete-related, concrete-unrelated, and abstract pictures. Functional (T2*-weighted) and anatomical (T1-weighted) images of the brain were obtained using a 1.5 T MRI scanner. The results in the younger adults showed that the left dorsal prefrontal cortex (PFC) was activated during associative learning of the concrete-unrelated or abstract pictures. The results also suggest that both ventral and dorsal visual pathways are involved in the encoding of abstract pictures, and that the right superior parietal lobule likely mediates spatial information of the abstract pictures. The older adults showed significant activation in the left dorsal PFC under concrete-unrelated and abstract conditions. However, the older adults failed to activate either the left ventral and right dorsal PFC under the concrete-unrelated condition, or the parietal areas under abstract condition. A direct comparison between the two age groups demonstrates that the older adults had a reduced activation in the bilateral parieto-temporo-occipital areas under abstract condition, and in the right temporo-occipital area extending to the fusiform gyrus under the concrete-unrelated condition. Finally, age difference was found in correlation between memory performance and amplitude of signal change in the parahippocampal gyrus and fusiform gyrus under the concrete-unrelated and abstract conditions. These changes in neural response likely underlie the age-related memory decline in relation to pictorial information.     

Does white matter matter? Spatio-temporal dynamics of task switching in aging

Older adults often encounter difficulties in switching between tasks, perhaps because of age-related decreases in executive function. Executive function may largely depend on connections between brain areas-connections that may become structurally and functionally weaker in aging. Here we investigated functional and structural age-related changes in switching between a spatial and a verbal task. These tasks were chosen because they are expected to differentially use the two hemispheres. Brain measures included anatomical information about anterior corpus callosum size (CC; the major commissure linking the left and right hemisphere), and the event-related optical signal (EROS). Behavioral results indicated that older adults had greater task-switching difficulties, which, however, were largely restricted to switching to the spatial task and to individuals with smaller anterior CCs. The EROS data showed both general switching-related activity in the left middle frontal gyrus (with approximately 300-msec latency) and task-specific activity in the inferior frontal gyrus, lateralized to the left for the switch-to-verbal condition and to the right for the switch-to-spatial condition. This lateralization was most evident in younger adults. In older adults, activity in the switch-to-spatial condition was lateralized to the right hemisphere in individuals with large CC, and to the left in individuals with small CC. These data suggest that (a) task switching may involve both task-general and task-specific processes; and (b) white matter changes may underlie some of the age-related problems in switching. These effects are discussed in terms of the hypothesis that aging involves some degree of cortical disconnection, both functional and anatomical.     

Neural correlates of auditory recognition under full and divided attention in younger and older adults

We examined how aging affects the pattern of brain activity mediating retrieval under dual-task conditions. We used functional magnetic resonance imaging (fMRI) to measure brain activity in younger and older adults while they were engaged in an auditory verbal recognition test under either full or divided attention (FA or DA). During recognition under FA, older adults had more activity in bilateral dorsolateral prefrontal cortex (PFC). DA with a distracting task requiring animacy judgments to words disrupted memory more than did a task requiring odd-digit judgments to numbers. For both behavioural and brain measures we contrasted the two DA conditions to recognition under FA to identify interference with memory performance. Behaviourally, there were no age differences in the magnitude of memory interference from DA conditions, although recognition performance was poorer overall in older adults. During the DA animacy condition, younger adults showed an increase in recognition latency, and older adults an increase in distracting task costs. Younger adults in this condition showed an increase in left inferior PFC, coupled with a decrease in right hippocampal activity; these effects were diminished in older adults who instead showed an increase in bilateral middle frontal activity. During both DA conditions, older adults showed greater activity in posterior neocortex compared to the younger group. Results indicate that older adults are able to perform as well as younger adults on retrieval tasks under DA conditions due to two alterations in brain activity: a dampening of the changes characterizing younger adults during the DA animacy condition and greater recruitment of additional regions during both DA tasks.     

Development of spatial and verbal working memory capacity in the human brain

A core aspect of working memory (WM) is the capacity to maintain goal-relevant information in mind, but little is known about how this capacity develops in the human brain. We compared brain activation, via fMRI, between children (ages 7-12 years) and adults (ages 20-29 years) performing tests of verbal and spatial WM with varying amounts (loads) of information to be maintained in WM. Children made disproportionately more errors than adults as WM load increased. Children and adults exhibited similar hemispheric asymmetry in activation, greater on the right for spatial WM and on the left for verbal WM. Children, however, failed to exhibit the same degree of increasing activation across WM loads as was exhibited by adults in multiple frontal and parietal cortical regions. Thus, children exhibited adult-like hemispheric specialization, but appeared immature in their ability to marshal the neural resources necessary to maintain large amounts of verbal or spatial information in WM.     

Working memory for complex scenes: age differences in frontal and hippocampal activations

Age differences in frontal and hippocampal activations in working memory were investigated during a maintenance and subsequent probe interval in an event-related fMRI design. Younger and older adults either viewed or maintained photographs of real-world scenes (extended visual or maintenance conditions) over a 4-sec interval before responding to a probe fragment from the studied picture. Behavioral accuracy was largely equivalent across age and conditions on the probe task, but underlying neural activations differed. Younger but not older adults showed increased left anterior hippocampal activations in the extended visual compared with the maintenance condition. On the subsequent probe interval, however, older adults showed more left and right inferior frontal activations than younger adults. The increased frontal activations at probe in older adults may have been compensatory for the decreased hippocampal activations during maintenance, but alternatively could have reflected the increased difficulty of the probe task for the older subjects. Thus, we demonstrate qualitatively different engagement of both frontal and hippocampal structures in older adults in a working memory task, despite behavioral equivalence.     

Age differences in target detection and interference resolution in working memory: an event-related potential study

There is growing consensus that a decline in attentional control is a core aspect of cognitive aging. We used event-related potentials to examine the time course of attentional control in older and younger adults as they attempted to resolve familiarity-based and response-based interference during a working memory task. Accuracy was high for both groups but their neural response to targets and to distracters was markedly different. Young adults' early target selection was evident by 300 msec in a differentiated P3a and they responded to interference by generating a medial frontal negativity (MFN) to distracters by 450 msec that was largest when the need for interference resolution was greatest. Dipole source analyses revealed a temporal coactivation of the inferior frontal and anterior cingulate cortex in younger adults, suggesting that these regions may interact during interference resolution. Older adults did not show the early target-selective P3a effect and failed to subsequently produce the MFN in response to distracting stimuli. In fact, older adults showed a large frontal positivity in place of the MFN but, rather than serve a compensatory role, this frontal activation was associated with poorer behavioral performance. These data suggest that aging interferes with a dynamic interplay of early target selection followed by later suppression of distracter-related neural activity--a process central to the efficient control of attention.     

Individual differences in verbal abilities associated with regional blurring of the left gray and white matter boundary

Blurring of the cortical gray and white matter border on MRI is associated with normal aging, pathological aging, and the presence of focal cortical dysplasia. However, it remains unclear whether normal variations in signal intensity contrast at the gray and white matter junction reflect the functional integrity of subjacent tissue. This study explores the relationship between verbal abilities and gray and white matter contrast (GWC) in healthy human adults. Participants were scanned at 3 T MRI and administered standardized measures of verbal expression and verbal working memory. GWC was estimated by calculating the non-normalized T1 image intensity contrast above and below the cortical gray/white matter interface. Spherical averaging and whole-brain correlational analyses were performed. Sulcal regions exhibited higher contrast compared to gyral regions. We found a strongly lateralized and regionally specific profile with reduced verbal expression abilities associated with blurring in left hemisphere inferior frontal cortex and temporal pole. Reduced verbal working memory was associated with blurring in widespread left frontal and temporal cortices. Such lateralized and focal results provide support for GWC as a measure of regional functional integrity and highlight its potential role in probing the neuroanatomical substrates of cognition in healthy and diseased populations.     

Event-related potentials of recognizing happy and neutral faces

In event-related potentials (ERPs) studies, recognition memory is associated with two positivities: one over parietal regions, and one over frontal regions. With nameable neutral stimuli, such as words or common objects, the parietal effect is usually left lateralized, and the frontal effect is usually right lateralized. We investigated the lateralization of these effects for nonnameable emotional stimuli: unfamiliar faces with happy and neutral expressions. The parietal effect was bilateral, suggesting that the left lateralization of this effect in studies using nameable stimuli reflected verbal processing. The frontal effect was left lateralized for happy faces, but right lateralized for neutral faces. This finding is consistent with the valence hypothesis, which posits that processing of pleasant emotions is lateralized to the left hemisphere.     

Verbal and spatial working memory in older individuals: A positron emission tomography study

Recent reviews of a substantial number of studies have partially resolved questions concerning the brain regions used by working memory for manipulation and representation. We report a large single experiment in middle-aged to older adults (n = 89), classified by hypertensive status. Our design addresses the question of regions related to manipulation and representation, most particularly comparing spatial and verbal working memory. A control, memory search, and 2-back running memory task were performed with identical stimuli and responses during whole-brain 15O water positron emission tomography (PET) scans. Letter or spatial position instructions created verbal or spatial working memory versions of the tasks. We assessed agreement with the literature using regions of interest that were defined by clusters of activation empirically derived from the literature by Wager and Smith (Wager, T.D. and Smith, E.E., Neuroimaging studies of working memory: a meta-analysis, Cognitive, Affective and Behavioral Neuroscience, 3 (2003) 255-274). Our results largely confirmed conclusions from the review on the organization of working memory into dorsal prefrontal manipulation and ventrolateral prefrontal maintenance areas and representation in dorsal and ventral paths. Specific verbal versus spatial comparisons were also concordant with prior work establishing posterior lateralized representation for different contents by working memory. The similarity of results between this older sample and results derived by others from younger participants is notable.     

Age-related changes in right middle frontal gyrus volume correlate with altered episodic retrieval activity

Age-related deficits in episodic retrieval have been associated with volume reductions in the middle frontal gyrus (MFG). However, it remains unclear how this age-related reduction in MFG volume correlates with neural activity during retrieval. To address this, we conducted in vivo volumetry of the frontal cortex in young and older human adults and found more volume loss on the right than on the left MFG with age. We then examined how left and right MFG volume correlated with fMRI activity during successful retrieval of item, spatial context, and temporal context information in both age groups. In young adults, larger right MFG volume was positively correlated with greater activity in a commonly found episodic retrieval network that included bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal cortex. Within this network, left DLPFC and right inferior parietal cortex activity predicted memory performance. In older adults, a positive structure-function association in DLPFC for either left or right MFG/DLPFC was not observed. Instead, right MFG volume was negatively correlated with activity in several regions in older adults, including the parahippocampal cortex (PHC) and anterior cingulate. Less activity in the PHC region predicted better item memory, and less activity in the anterior cingulate predicted better spatial context accuracy in older adults. We conclude that age-related change in the structure-function association in MFG/DLPFC impacts retrieval activity and performance, and those older adults with larger right MFG volume attempt to compensate for this change by modifying activity in other brain regions to help retrieval performance.     

A "concrete view" of aging: event related potentials reveal age-related changes in basic integrative processes in language

Normal aging is accompanied by changes in both structural and functional cerebral organization. Although verbal knowledge seems to be relatively stable across the lifespan, there are age-related changes in the rapid use of that knowledge during on-line language processing. In particular, aging has been linked to reduce effectiveness in preparing for upcoming words and building an integrated sentence-level representation. The current study assessed whether such age-related changes extend even to much simpler language units, such as modification relations between a centrally presented adjective and a lateralized noun. Adjectives were used to elicit concrete and abstract meanings of the same, polysemous lexical items (e.g., "green book" vs. "interesting book"). Consistent with findings that lexical information is preserved with age, older adults, like younger adults, exhibited concreteness effects at the adjectives, with more negative responses to concrete adjectives over posterior (300-500 ms; N400) and frontal (300-900 ms) channels. However, at the noun, younger adults exhibited concreteness-based predictability effects linked to left hemisphere processing and imagery effects linked to right hemisphere processing, contingent on whether the adjectives and nouns formed a cohesive conceptual unit. In contrast, older adults showed neither effect, suggesting that they were less able to rapidly link the adjective-noun meaning to form an integrated conceptual representation. Age-related changes in language processing may thus be more pervasive than previously realized.     

Age differences in prefontal recruitment during verbal working memory maintenance depend on memory load

Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies have revealed age-related under-activation, where older adults show less regional brain activation compared to younger adults, as well as age-related over-activation, where older adults show greater activation compared to younger adults. These differences have been found across multiple task domains, including verbal working memory (WM). Curiously, both under-activation and over-activation of dorsolateral prefrontal cortex (DLPFC) have been found for older adults in verbal WM tasks. Here, we use event-related fMRI to test the hypothesis that age-related differences in activation depend on memory load (the number of items that must be maintained). Our predictions about the recruitment of prefrontal executive processes are based on the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH; Reuter-Lorenz and Cappell, 2008). According to this hypothesis, more neural resources are engaged by older brains to accomplish computational goals completed with fewer resources by younger brains. Therefore, seniors are more likely than young adults to show over-activations at lower memory loads, and under-activations at higher memory loads. Consistent with these predictions, in right DLPFC, we observed age-related over-activation with lower memory loads despite equivalent performance accuracy across age groups. In contrast, with the highest memory load, older adults were significantly less accurate and showed less DLPFC activation compared to their younger counterparts. These results are considered in relation to previous reports of activation-performance relations using similar tasks, and are found to support the viability of CRUNCH as an account of age-related compensation and its potential costs.     

Memory Performance in Older Adults Before and After Temporal Lobectomy for Pharmacoresistant Epilepsy

Little is known about the effects of epilepsy surgery on memory in older adults. The purpose of this study was to determine if older adults exhibit greater memory decline than younger adults after anterior temporal lobectomy (ATL). Patients 55 years and older at time of surgery (23 left, 14 right ATL, range 55–66 years) were compared to patients age 25–35 years (44 left, 33 right ATL) to assess differences in preoperative to postoperative change in WMS-III index scores. Repeated-measures ANOVAs and ANCOVAs revealed that older patients did not demonstrate greater decline than younger patients across any of the memory indices. Rather, in the left ATL group, older patients showed less decline than younger patients on the Auditory Delayed Memory Index. Similarly, in the right ATL group, older patients showed less decline than younger patients on the Visual Delayed Memory Index. These patterns were also apparent in frequency of individual change. Results provide preliminary evidence that older adults who are good candidates for ATL are not at greater risk for memory decline when measured at 7 months postoperatively.     

Effects of aging on true and false memory formation: an fMRI study

Compared to young, older adults are more likely to forget events that occurred in the past as well as remember events that never happened. Previous studies examining false memories and aging have shown that these memories are more likely to occur when new items share perceptual or semantic similarities with those presented during encoding. It is theorized that decreased item-specific encoding and increased gist encoding contribute to these age differences in memory performance. The current study used a modified version of the Deese–Roediger–McDermott (DRM) paradigm to investigate the neural correlates of true and false memory encoding. Results indicated that, compared to young, older adults showed reduced activity in medial temporal lobes (MTL), left ventrolateral prefrontal cortex (VLPFC), and visual cortices associated with subsequent true memories. Despite these decreases older adults showed increased activity in right VLPFC and left superior temporal gyrus (STG) for subsequent true memories. Age-related increases in STG were also associated with subsequent false memories. Results support the theory that older adults engage in less item-specific encoding and greater gist encoding, and that these increases in gist encoding support both subsequent true and false memories. Furthermore, results extend findings of reduced frontal asymmetry in aging, often found in block designs, to the subsequent memory paradigm. Results suggest that greater bilateral frontal activity during encoding in aging are not just task-related, but may be associated with subsequent successful memory performance.     

The neurodevelopmental differences of increasing verbal working memory demand in children and adults

Working memory (WM) – temporary storage and manipulation of information in the mind – is a key component of cognitive maturation, and structural brain changes throughout development are associated with refinements in WM. Recent functional neuroimaging studies have shown that there is greater activation in prefrontal and parietal brain regions with increasing age, with adults showing more refined, localized patterns of activations. However, few studies have investigated the neural basis of verbal WM development, as the majority of reports examine visuo-spatial WM.We used fMRI and a 1-back verbal WM task with six levels of difficulty to examine the neurodevelopmental changes in WM function in 40 participants, twenty-four children (ages 9–15 yr) and sixteen young adults (ages 20–25 yr). Children and adults both demonstrated an opposing system of cognitive processes with increasing cognitive demand, where areas related to WM (frontal and parietal regions) increased in activity, and areas associated with the default mode network decreased in activity. Although there were many similarities in the neural activation patterns associated with increasing verbal WM capacity in children and adults, significant changes in the fMRI responses were seen with age. Adults showed greater load-dependent changes than children in WM in the bilateral superior parietal gyri, inferior frontal and left middle frontal gyri and right cerebellum. Compared to children, adults also showed greater decreasing activation across WM load in the bilateral anterior cingulate, anterior medial prefrontal gyrus, right superior lateral temporal gyrus and left posterior cingulate. These results demonstrate that while children and adults activate similar neural networks in response to verbal WM tasks, the extent to which they rely on these areas in response to increasing cognitive load evolves between childhood and adulthood.     

Working memory representation in atypical language dominance

One of the most important factors controlling material specific processing in the human brain is language dominance, i.e. hemispheric specialization in semantic processes. Although previous studies have shown that lateralized long-term memory processes in the medial temporal lobes are modified in subjects with atypical (right) language dominance, the effect of language dominance on the neural basis of working memory (WM) has remained unknown. Here, we used functional MRI (fMRI) to study the impact of language dominance on the neural representation of WM. We conducted an n-back task in three different load conditions and with both verbal and nonverbal (spatial) material in matched groups of left and right language dominant subjects. This approach allowed us to investigate regions showing significant interactions between language dominance and material. Overall, right dominant subjects showed an increased inter-individual variability of WM-related activations. Verbal WM involved more pronounced activation of the left fusiform cortex in left dominant subjects and of the right inferior parietal lobule in the right dominant group. Spatial WM, on the other hand, induced activation of right hemispheric regions in left dominant subjects, but no specific activations in right dominant subjects. Taken together, these findings indicate that the neural basis of verbal WM processes depends on language dominance and is more mutable in right dominant subjects. The increased variability in right dominant subjects strongly suggests that a standard network of material-dependent WM processes exists in left dominant subjects, and that right dominant subjects use variable alternative networks.     

Is the prefrontal cortex necessary for delay task performance? Evidence from lesion and FMRI data.

Although the prefrontal cortex (PFC) is consistently found to be associated with various working memory processes, the necessity of the PFC for such processes remains unclear. To elucidate PFC contributions to storage and rehearsal/maintenance processes engaged during verbal working memory function, we assessed behavior of patients with lesions to the left or right lateral PFC, and neural activity of healthy young subjects during fMRI scanning, during performance of working memory tasks. We found that PFC lesions did not affect storage processes--which is consistent with the notion that posterior cortical networks can support simple retention of information. We also found that PFC lesions did not affect rehearsal/maintenance processes, which was in contrast to our finding that healthy subjects performing a verbal delayed recognition task showed bilateral PFC activation. These combined imaging and behavioral data suggest that working memory rehearsal/maintenance processes may depend on both hemispheres, which may have implications for recovery of function and development of rehabilitation therapies after frontal injury.     

The neural correlates of attention orienting in visuospatial working memory for detecting feature and conjunction changes

The neural mechanisms of attentional orienting in visuospatial working memory for change detection were investigated. A spatial cue was provided with the onset time manipulated to allow more effective top-down control with an early cue than with a late cue. The change type was also manipulated so that accurate detection depended on color or the binding of color and location. The results showed that both the frontal and parietal regions subserved the change detection task without cueing. When data were collapsed over the two change types, early cueing increased activation in the right inferior frontal gyrus (IFG) and middle frontal gyrus (MFG) while late cueing increased activation in the right inferior parietal lobule (IPL) and temporoparietal junction (TPJ) as compared with the no-cue condition. The cue onset time led to different levels of enhancement in the frontal and posterior cortices related to top-down control and stimulus-driven orienting. For feature detection, early cueing increased activation in the right MFG and late cueing increased activation in the bilateral precuneus (PCu), right TPJ, and right cuneus. The neural correlates of conjunction detection involved the right PCu and cerebellum without cueing, were associated with the anterior MFG, left IFG, and the left STG with early cueing, and involved the right MFG, left IFG, and right IPL with late cueing. The left IFG was correlated with memory retrieval of the cued representation for conjunction detection, and the right posterior PCu was associated with maintenance and memory retrieval among competing stimuli.