A large body of literature suggests that episodic memory processes, particu- larly encoding and retrieval, decline with age.26-31 Whether this is related to
“normal aging” of the brain or to an accumulation of age-related diseases remains a topic of some debate.32–34 There is some evidence to suggest selec- tive age-related atrophy of prefrontal cortical areas involved in episodic memory circuitry,35 with relative preservation of medial temporal lobe structures,35–37 although this too is debatable.38–40 Furthermore, regenera- tive processes and reorganization in the adult human brain may help allay development of cognitive problems despite structural brain changes.41,42 Therefore, significant questions remain as to the neural and cognitive basis of episodic memory decline in aging.
A number of functional neuroimaging, electrophysiological, and behav- ioral studies suggest that the typical prefrontal functional asymmetries for memory processes in younger adults are diminished or absent in older adults. In other words, research suggests that the HERA model does not hold in normal aging. This concept has been articulated in the Hemispheric Asymmetry Reduction in Old Adults (HAROLD) model.43 Increased bilateral
Table 7.1.Sample fMRI Task Characteristics for Episodic, Semantic, and Working Memory Study Memory domain
Cognitive processModalityDesignStimuliaControl conditionPerformance monitoring Logan et al., 200246Episodic memoryIntentional & inci- dental encodingVisualBlockedWords and facesFixation stimulusSs completed a recognition test
immediately after
presentation of the stimuli Saykin et al., 177771Semantic memoryCategory-matchingAuditoryBlockedWord pairs: category- exemplar pairs (e.g., beverage-milk; vehicle-carrot) and
category-function pairs
(e.g., beverage- sip, beverage-debate)
Separate pho-
nological task
using nonword- matching (e.g.,
temla-temla; yodb-r
ea)
Ss pressed a pneu- matic bulb in scanner to indi- cate whether the word pairs matched or not Rypma &
D’Esposito, 2000
104
Working memoryDelayed responseVisualEvent-relatedA series of memory sets containing either 2 or 6 stimuli (letters, or objects and loca- tions) were encoded and retained over an unfilled interval
Ss indicated in scanner whether a single item was or was not part of the memory set just presented aIn all three cases, the different types of stimuli were presented in different runs, e.g., words on one run, faces on another.
representation of cognitive functions in older adults may reflect a form of compensatory brain re-organization that helps support normal cognitive function. This would parallel findings on brain functional reorganization following acquired brain damage. For example, in the case of unilateral focal acquired brain damage, recovery of function can be associated with bihemi- spheric representation (among other types of reorganization) for functions such as language and movement.44,45 On the other hand, bihemispheric rep- resentation simply may reflect diminished selectivity or de-differentiation of the neural substratRef48 e of cognition in older adults,46,47 which may or may not be partly consistent with an interpretation based on compensation, depending on investigators’ use of these terms.
A small number of recent fMRI studies speak to the HAROLD model and address issues of compensation versus de-differentiation of the neural sub- strate of episodic memory in aging. For example, Morcom and colleagues48 observed overall activation of inferior prefrontal cortex and the hippocam- pal formation for successful recognition of previously presented words.
Activation was relatively left-lateralized in the younger adults, and more bilaterally represented in the older group (Figure 7.1).
Logan and colleagues46 investigated the brain basis of episodic memory in two fMRI experiments in younger and older adults. Older adults showed less hemispheric asymmetry for intentional encoding of both verbal and nonverbal material, with greater right prefrontal (Brodmann areas 6/44) activation for words, and greater left prefrontal (BA 6/44) activation for face encoding compared to young adults. In this study, failure to recruit normal task-related areas did not always occur in conjunction with recruit- ment of additional brain regions, suggesting that these two types of altera- tion in brain activity may occur independently in aging. Furthermore, this
Figure 7.1. Brain regions showing age-related differences in activity during success- ful recognition of previously presented verbal information. Young adults showed greater activation than older adults in left anterior inferior temporal cortex (BA 20) (A). Older adults showed greater activation than young adults in bilateral anterior prefrontal cortex among other regions (B). Reprinted from Morcom AM, Good CD, Frackowiak RS, et al. Age effects on the neural correlates of successful memory encoding. Brain. 2003;126(Pt 1):213–227, by permission of Oxford University Press.
(Neurologic coordinates).
study provided preliminary evidence that strategy use could overcome the age-related changes in brain activity. During intentional encoding of words, older adults failed to activate a left prefrontal (BA 45/47) region recruited by young adults (Figure 7.2A,B); this is an area thought to be associated with semantic elaboration and successful verbal encoding. However, when supported in the use of deep encoding strategies, activation of this region in older adults approximated that of controls (Figure 7.2C,D). These find- ings suggest that the regional deficit in activation in older adults during encoding is related to inefficient recruitment of available brain resources, rather than an irreversible loss of the underlying tissue due to cell death or dysfunction.
In a related study, Daselaar and colleagues47 found that healthy older adults activated mainly left frontotemporal and cingulate areas during deep relative to shallow classification, similar to young adults. However, the older adults showed under-recruitment of left anterior hippocampus relative to the young adults. The authors interpreted this as possible evidence that, despite the capacity to engage brain regions associated with semantic elabo- ration, age-related impairment of medial temporal system functioning may nonetheless hinder episodic encoding in older adults.
Krause and colleagues4 reported greater prefrontal connectivity during episodic encoding and retrieval in older adults compared to younger adults on structural equation modeling of fMRI and position emission tomography (PET) data, which lends some further support to the HAROLD model.50 Furthermore, Krause and colleagues found stronger connectivity involv- ing inferior parietal cortex and less for the hippocampal formation in older compared to younger subjects, consistent with an age-related change in the neural circuitry underlying episodic memory.
Whereas many studies of cognitive aging have used auditory–verbal or spatial stimuli, memory for which generally declines with age, Iidaka and colleagues examined brain activation patterns associated with pictorial memory using fMRI.51 Based on prior findings that memory for pictures is generally better than memory for words and is relatively preserved in normal aging (especially memory for concrete and meaningful pictorial information), Iidaka and colleagues compared brain activity associated with encoding pairs of concrete-related, concrete-unrelated, and abstract pictures.
The concrete-related task made relatively simple cognitive demands (e.g., learning to associate a picture of a cigarette with a picture of an ashtray) and yielded little significant signal change relative to the control condition. The main findings involved the unrelated and abstract pictures. Briefly, both the younger and older participants showed activation of left dorsal prefrontal cortex during encoding of the concrete-unrelated pictures and the abstract pictures. However, compared to the young group, the older adults showed reduced activation in some regions, including right temporo-occipital cortex in the concrete-unrelated condition and bilateral parieto-temporo-occipital areas during abstract picture encoding. There were no regions in which older adults showed greater signal change than controls, providing no evidence of compensatory processing or de-differentiation in the older group, possibly related to the relatively preserved figural recall performance of the older adults on baseline cognitive testing.
In an fMRI study of remote memory in older adults, Haist and colleagues52 suggested a preferential role for the entorhinal cortex in consolidation of
Figure 7.2. Brain regions showing age-related differences in activation during encoding of verbal material. Images are presented in neurologic coordinates (left side of brain shown on left side of image), with arrows marking the regions being highlighted. In Experiment 1, young adults showed activation of left BA 45/47 dur- ing intentional encoding of words, whereas older adults showed under-recruitment of this region (A). In Experiment 2, this pattern was replicated (B). When older adults were supported in the use of semantic elaboration, under-recruitment of BA 45/47 was reversed (C), but non-selective activation of right BA 6/44 remained (D).
Reprinted from Neuron, Vol. 33, Logan JM, Sanders AL, Snyder AZ et al. Under- recruitment and non-selective recruitment: dissociable neural mechanisms associ- ated with aging, 827–840, Copyright © 2002, with permission from Elsevier.
memory over decades. They presented eight older adults with pictures of famous faces from each decade from the 1740s to the 1770s and compared the brain activity to activation patterns for nonfamous faces from the present and the past. While the hippocampus was activated during recognition of the more recent famous faces, parahippocampal activity was present for famous faces from several of the recent and past decades, and right entorhi- nal activation appeared to be associated with memory for faces extending up to two decades back in time. Although the finding was preliminary, the authors interpreted it as consistent with evidence that damage to the CA1 hippocampal subfield results in a retrograde amnesia of a few years, whereas more-extensive temporal lobe involvement causes a longer period of retrograde amnesia. It is noteworthy that lesion studies typically have reported widespread temporal lobe damage in cases of pronounced retro- grade amnesia.53,54
In a study of real autobiographical event memories acquired over dec- ades, Maguire and Frith55 found that younger and older adults activated a similar broad network of regions with one key difference—whereas the younger participants activated the left hippocampus during retrieval, older participants activated the hippocampus bilaterally. This additional hippocampal recruitment was evident despite preserved performance in both groups and was specific to the autobiographical event memories.
The authors discuss possible explanations for the finding, including pos- sible increased salience of the spatial context for the memories in the older adults, the fact that older adults have accrued more memories that need to be distinguished, and the possibility that the right hippocampus activated as a compensatory mechanism.
Small and colleagues have used a blood oxygenation level-dependent (BOLD) fMRI signal obtained at rest to estimate regional basal metabolism and examine the integrity of hippocampal subregions in healthy controls and individuals with dementia.56,57 This method rests on the assumption that basal deoxyhemoglobin levels reflect hemodynamic variables, such as oxygen extraction, that are related to basal metabolism. Using this method, Small examined hippocampal circuitry in 70 individuals ranging in age from 20 to 88 years. In two hippocampal subregions, the subiculum and the den- tate gyrus, decline in resting BOLD fMRI signal appeared to occur as a linear function of age. However, decline in the entorhinal cortex was more variable, present only in a subset of older adults. This was interpreted as evidence that the entorhinal change was not a normal age-related change, but rather an indicator of a pathological process.
Although limited at this point to cross-sectional data, fMRI research sug- gests a variety of age-related changes in episodic memory circuitry. This includes reduced prefrontal asymmetry, greater prefrontal connectivity, and altered frontal–medial temporal activity and interaction, among other changes. Although structural brain changes may well play a role in induc- ing age-related changes in activity of episodic memory circuitry, the studies that compared deep to shallow encoding46,47 offer preliminary evidence that age-related differences in the approach to a task may also contribute to the inducement of age-related changes. This underscores the importance of incor- porating both structural and functional brain imaging methods in studies of cognition and aging, and of carefully monitoring participants’ cognitive strategy use or approach to the task in addition to other aspects of their task performance.