Reduced ERC volume has been shown in numerous studies to be associated with AD (Pennanen et al., 2004
; Xu et al., 2000
) and risk for AD (deToledo-Morrell et al., 2004
; Dickerson et al., 2001
; Killiany et al., 2002
; Stoub et al., 2005
). In the current study, we used left ERC thickness as an indicator of increased AD risk, and examined its relationship with fMRI activity during encoding and retrieval in an associative memory task. During attempted memory retrieval, older adults having thicker left ERC showed greater fMRI activity in anterior cingulate (BA 24 & 32) and medial frontal (BA 9 & 10) cortices than those having thinner left ERC. These results were independent of age, task performance, and hippocampal volume. Our results suggest that there are functional consequences to structural thinning of ERC and that processes specific to attempted memory retrieval are particularly sensitive to ERC integrity.
Layers V and VI of ERC are strongly connected to anterior cingulate cortex in non-human primates (Arikuni et al., 1994
; Munoz and Insausti, 2005
). Furthermore, in the rhesus monkey there are direct connections between anterior cingulate (BA 24 & 32) and medial frontal (BA 9 & 10) cortices (Barbas and Pandya, 1989
). Therefore, the significant correlation between ERC structure and activity in anterior cingulate and medial frontal cortices is consistent with the known anatomical connectivity of these regions.
On average, across subjects, anterior cingulate cortex showed increased activation during attempted memory retrieval, which is consistent with several past studies (Buckner et al., 1996
; Cabeza et al., 2003
; Gould et al., 2003
). The portion of medial frontal cortex that was preferentially activated in those with thicker left ERC was not active on average during memory retrieval, however, because approximately half of the participants showed a negative percent signal change in that region, diluting the overall percent signal change across the group. During both episodic memory encoding and recognition, previous researchers found that compared with younger adults, older adults showed less task-induced deactivation in medial frontal cortex (Grady et al., 2006
). The question arises then, if older adults with thicker ERC (in the current study) are presumably more like younger adults, why do they have greater activation during task, while young adults previously showed greater deactivation during task? One possible explanation for our results is that those older adults having thicker ERC were better able to recruit medial frontal cortex to compensate for unspecified age-related deficits in the brain (such as changes in neurotransmitter systems). Because we included only cognitively intact older adults in this study, all subjects must be successfully compensating in some way for any age-related cognitive deficits that they may have, so it is not surprising that the behavioral effect of such compensation is not evident in our sample. Our results are consistent with those of a recent study finding that during an episodic recognition task, cognitively intact middle-aged adults with lower AD risk showed greater fMRI activation in anterior cingulate and medial frontal cortices compared with those having increased AD risk (Xu et al., 2008
Many past studies of cognitively intact older adults have examined the relationship between increased AD risk and fMRI activity during a memory or novelty encoding task, primarily using increased genetic risk for AD (Bondi et al., 2005
; Bookheimer et al., 2000
; Dickerson et al., 2005
; Fleisher et al., 2005
; Han et al., 2006
; Trivedi et al., 2006
; Wishart et al., 2006
) or family history of AD (Bassett et al., 2006
) as indicators of increased AD risk. Most of these studies did not report the individual relationship during memory retrieval (versus control period) between increased AD risk and whole brain fMRI activation. As in our study, one study by Bassett et al. (2006)
reported that during retrieval of word pairs, those who had lower risk for AD activated more in regions that included anterior cingulate cortex (BA 24 & 32) and middle frontal gyrus (BA 9) (although more laterally than in the current study).
In a study similar to ours, Rosen et al. (2005)
examined the relationship in older adults between left ERC volume and functional activity during incidental encoding of individual words. They found that frontal activity during encoding was greater in those with greater left ERC volume, but this increased activation was in right BA 47/insula rather than in anterior cingulate and medial frontal cortices as in our study. Additionally, we found a significant relationship between ERC thickness and fMRI activity during attempted retrieval, but not encoding. However, our studies differ methodologically in several ways, including task, measure of ERC atrophy, age, and sample size. Specifically, during scanning, subjects in the study by Rosen et al. (2005)
were instructed to make semantic judgments about words presented to them, but were not instructed to remember those words. They were later tested on their memory for the words outside the scanner. In contrast, our subjects were instructed to encode pairs of words and were later scanned while being cued with the first word in order to recall its mate. It is therefore not surprising that such different tasks resulted in variations of activation. Additionally, our subjects were on average nearly 10 years younger and spanned a wider age range than in the Rosen and colleagues study. Finally, the previous study contained only 13 subjects, while ours examined 32; some of the differences between our study and theirs may be due to normal variations associated with subject selection for a small sample size (Rosen et al., 2005
As in our study, previous research using a verbal paired associates task found a more pronounced relationship between fMRI activity and AD risk during retrieval than during encoding (Bookheimer et al., 2000
). This is to be expected because, although recollection shares many attributes of memory encoding (including encoding itself), it also involves additional processes that memory encoding lacks, such as using a cue to derive the associated word, response selection and monitoring, and blocking of distracting information in order to arrive at the correct answer.
Our data provide evidence that the structural integrity of ERC contributes to functional brain activity during an associative recollection task. The same words were presented six times throughout the encoding task, but we did not see a significant correlation between ERC thickness and fMRI activity during encoding. This suggests that our results were not solely due to the familiarity of the cue words presented at retrieval. Our results support our hypothesis that even during an associative task, retrieval attempts in older adults were mediated by a circuit that includes ERC and frontal lobe, and that ERC integrity played a role in this relationship.
Anterior cingulate cortex is believed to be associated with response monitoring, in particular for evaluating possible errors. Such monitoring may be beneficial in updating memory strategies (Rushworth, 2008
). Functional activity in anterior cingulate cortex and in BA 9 & 10 has been implicated in recognition success (Konishi et al., 2000
; Rugg et al., 1996
). Additionally, activity in anterior prefrontal regions during recognition (success and failure) has a late onset and sustained duration, suggesting that like anterior cingulate cortex, this region is involved in post-retrieval monitoring (Schacter et al., 1997
). The fact that both anterior cingulate cortex and BA 10 have been shown to activate more during memory retrieval when a participant is less confident in his or her response offers further support for their role in response monitoring (Fleck et al., 2006
). Although response monitoring is important for adjusting strategy to meet the needs of a given task, it is only one aspect of the processes involved in encoding and recalling information. Additionally, in older adults, factors other than ERC thickness (such as education or age-related deficits in neurotransmitter systems) may affect memory ability (Volkow et al., 1998
). This may explain why ERC thickness and fMRI function were not related to score on the paired associates memory task. Had we not limited our study to cognitively intact adults, which limits the range of cognition to those who are by definition successfully compensating for cognitive stressors, the relationship between ERC thickness and cognition may have been detectable.
Although ERC provides major inputs to the hippocampus, we did not find a significant relationship between ERC thickness and hippocampal fMRI activity. However, the hippocampus is composed of subregions that may be recruited differently during a given memory task (Zeineh et al., 2003
), and that are differently susceptible to AD-related pathology (Braak and Braak, 1991
) and degeneration (Bobinski et al., 1998
). Accurate identification and coregistration of these small subregions across subjects is difficult with standard fMRI scans. Using scans optimized for detecting fMRI activity in specific hippocampal subregions may have facilitated exposing such a relationship, if one existed.
The brain's response to error detection has been shown to change with aging (Falkenstein et al., 2001
), and error detection is impaired with AD (Bettcher et al., 2008
). The current study provides a mechanism by which changes to medial temporal lobe may be linked to changes in frontal lobe function in older adults at risk for AD. Specifically, ERC thickness in older adults appears to modify the ability to engage anterior cingulate and frontal regions believed to be important in error detection and other post-retrieval processing. ERC volume is smaller in those having AD, but not in those who are aging normally (Fukutani et al., 2000
; Giannakopoulos et al., 2003
; Gomez-Isla et al., 1996
; Hof et al., 2003
; Kordower et al., 2001
; von Gunten et al., 2006
). However, AD risk also increases with age. Therefore, particularly in older adults, thinner ERC may suggest cortical degeneration even in some cognitively intact adults. We do not suggest that all people having thin ERC are preclinical for AD, but rather that thin ERC in older adults increases the likelihood of preclinical AD, including in some older adults believed to be aging normally. This study is cross-sectional rather than longitudinal, so we do not know which of the subjects in this study will eventually develop AD. Because those participants with thinner ERC are at higher risk for AD, however, these data provide a framework with which to examine current and future studies of AD risk.
The relationship between ERC thickness and fMRI activity was not different in those having larger versus smaller hippocampal volumes. Additionally, after adjusting for age, hippocampal volume was not significantly associated with fMRI activity during encoding or retrieval. This suggests that if the greater fMRI activity we saw in those with thicker ERC was in compensation for deficits elsewhere in the brain, those deficits were not related to age-associated overall hippocampal atrophy. It is possible that measurements of selected hippocampal regions would be a more sensitive grouping mechanism when evaluating these relationships. It is also possible that the increased fMRI activity in those with thicker ERC instead compensates for deficits in frontal lobe function, which is known to decline with age (Cohen et al., 1987
; De Luca et al., 2003
; Gazzaley et al., 2005
). Such changes may relate to changes in neurotransmitter synthesis and processing, which are believed to occur in older adults (Adolfsson et al., 1979
; Cruz-Muros et al., 2007
; Goldberg et al., 2004