In the current study, we compared BOLD response for correct recent versus correct remote retrieval of non-autonoetic, associate memories. We used this data to explicitly test each of seven specific hypotheses derived from current systems level consolidation theory. The experimental analysis allowed us to compare not only the coarse-grain (between session) temporal dynamics, but finer-grain (within trial sub-component) dynamics as well. In general, we confirmed five of the seven predictions of the extended theory and found at least some evidence for the remaining two.
Systems level consolidation increased recall related activity in left lateral temporal regions associated with the modality of the stimuli being remembered and increased connectivity between these regions. While substantial volumes of the lateral temporal lobes were active in individual analysis of both sessions (not shown), the regions identified as increasing with consolidation were only robustly active in the remote memory condition and were not active in the recent memory condition (). This finding is consistent with the hypothesis that the memories have been at least partially consolidated to this region. Visual regions (inferior temporal/fusiform gyri) were identified as more active during the visual cue period while polymodal regions (middle temporal) were identified as more active later during the delay period consistent with the visual-then-auditory nature of the task and the supposition that sensory processing regions are involved in long-term memory storage. Connectivity between these two regions increased in the second session even after the main task effect was removed. Systems level consolidation also decreased functional connectivity between the left lateral temporal region and a peak within the medial temporal ROI, which was identified as likely within the hippocampus. Consolidation also increased functional connectivity between the left lateral temporal region and the left prefrontal cortex. This is consistent with the hypothesized reduction of the role of the medial temporal memory network in coordinating recall of sensory information in remote memory and an increase in the role of the prefrontal cortex. Again, the changes in connectivity are beyond that explainable by correlations due to the consistent task effect and thus reflect additional confirmations of the extended theory's hypotheses.
Within the medial temporal lobes, the results were less directly in line with the theoretical predictions; increases and decreases related to one month of experience were observed in this region. Medial temporal regions showing larger BOLD response in the recent than remote session were identified as likely within the hippocampus and perirhinal cortex. This localization is in agreement with other data with greater spatial resolution. Previous lesion studies have focused on the CA fields as a primary location of consolidation related reductions within the hippocampus proper (Bontempi et al., 1999
) and the perirhinal cortex is known to be involved in delayed matching paradigms and paired associate memory in particular (Miyashita et al., 1996
, 1998; Rolls and Kesner, 2006
). A different region also probabilistically localized to the hippocampus was active above fixation baseline in the visual cue period of the remote condition only. Further study using a similar experimental paradigm at a much higher spatial resolution and focused specifically on the hippocampal region (at the expense of other regions) would be necessary to determine if the substructures of the hippocampus are differentially affected by systems consolidation.
Consolidation increased recall-related activity in prefrontal cortex bilaterally. The left prefrontal region was located in the vicinity of the pars opercularis, putative BA 44, an area strongly implicated in phonological and auditory processing (Romanski et al., 1999
; Poldrack et al., 2001
) and auditory working memory storage (Baddeley, 2003
). This region was significantly active for both recent and remote memory, likely indicating its role in the working memory requirements of the task. The region increased activation and increased functional connectivity with the lateral temporal region during remote relative to recent memory recall. The increase in activity and connectivity is consistent with the hypothesis that this region is involved in the coordination of recall related activity as well since the working memory requirements of the task did not differ between sessions. The activation and connectivity results are in agreement with previous reports in nonhuman primates identifying coordinated activity between inferior temporal and prefrontal regions being necessary for memory recall (Eacott and Gaffan 1992
; Gutnikov et al, 1997
The right inferior frontal ROIs were putatively located in right Brodmann's area 47, a region that has been implicated in a number of memory processes including non-spatial working memory (Smith and Jonides, 1999
). This region was only robustly active in the remote memory condition. These right frontal regions were more connected to the lateral temporal regions during the recent than remote memory recall session and more connected to the medial temporal memory system, including the putative hippocampus, in the remote than recent session. Since neither this prefrontal ROI nor the lateral temporal ROI were robustly active across subjects in the recent memory condition, it is unclear what greater connectivity in the recent condition indicates. It is possible that the correlation in the recent condition is not related to the trial-to-trial variability but to some other activity unrelated to the task such as “revisiting” the stimulus pairing or evaluating the response during the inter-trial interval.
Brodmann area 47 has been implicated in response suppression, including memory suppression, in both lesion and imaging studies (Aron et al., 2004
). While BA47 is not the region implicated as having a direct role suppressing the hippocampus in animal models, it is possible that this region mediates suppression of the hippocampal region via strategic control. This potentially explains the increased connectivity between this region and the inactive portions of the hippocampal complex in the remote memory condition. It also possibly explains the larger connection in the recent session between the right prefrontal region and the lateral temporal region if right prefrontal cortex was suppressing lateral temporal involvement in the not-yet consolidated memory recall. However, this type of causal role cannot be directly determined from the correlation results and is perhaps beyond the types of memory suppression previously reported.
The increases and decreases seen in the medial temporal and other regions may not be completely due to consolidation related effects. The one month consolidation period used in the current study, though previously demonstrated to be of sufficient length to observe consolidation related effects (c.f. Takashima et al., 2006
), was unlikely to be sufficient to complete the consolidation process. If considerable learning occurred in the 2 week reminder session, some “remote” memories may be as little as two weeks old. Thus the increase observed in the vicinity of the hippocampus may simply be due to continued consolidation processes or continued learning of the item pairs or other incidental learning.
Numerous studies have observed differential effects within the medial temporal lobes when contrasting encoding and recall related activity (c.f., Zeineh et al., 2003
; Eldridge et al., 2005
). In the current study, training occurred outside the scanner and subjects achieved a high level of accuracy. During scanned testing, no feedback was given and correct responses to both correct and incorrect pairings were analyzed. Thus any encoding related activity observed was likely to be incidental (e.g., trial ordering, incorrect pairings etc.). There is no a priori reason this incidental encoding should differ between sessions. Still, a reduction in encoding related processing remains a potential explanation for the medial temporal decrease and a potential confound for the current study. It is not clear, however, how this interpretation explains the medial temporal increase seen in the visual cue. An encoding/retrieval interpretation of this increase would suggest that subjects retrieved “more” during the remote condition when they were numerically less accurate and trended toward decreased sensitivity. While this might indicate more “effortful” retrieval related activity, such an interpretation seems contradictory to a previous study showing a positive correlation of medial temporal activity with accuracy during the retrieval phase (Zeineh et al., 2003
Encoding versus retrieval could also be argued to potentially explain the prefrontal results. The hemispheric encoding retrieval asymmetry (HERA) model has been used to describe differences in prefrontal activity during encoding and retrieval (Tulving et al., 1994
, Nyberg et al., 1996
). Though not without controversy (c.f Miller et al., 2002
), HERA theory states that memory encoding preferentially activates left prefrontal regions while recall activates right prefrontal regions. Thus, the increased right prefrontal activity during the remote condition may simply reflect increased recall related processes rather than consolidation related effects. However, the left prefrontal cortex also increased from the recent to the remote session, contrary to this interpretation. It is not clear how both encoding and retrieval could have increased in the remote session though perhaps a re-encoding of partially forgotten visual stimuli is possible. Further, it is unclear how such an interpretation explains the decreased connectivity between the right prefrontal region and the lateral temporal region, which would presumably increase if the right prefrontal activity reflected recall. Nor does the HERA model encoding/retrieval interpretation seem consistent with the increased left prefrontal and lateral temporal connectivity unless encoding processes also increased for remote memory recall. As with the hippocampal complex results, studying both learning and consolidation simultaneously may help to better disambiguate these issues.
A related alternative explanation is an effect of memory type and/or memory strength. Differential recall effects have been described within the medial temporal lobes with the hippocampus proper associated with explicit memory recall and perirhinal cortex and other structures associated with feelings of familiarity (Brown and Aggleton, 2001
). It is possible that a change in the level of explicit recall between the recent and remote sessions may explain the medial temporal increase and decrease observed here. However it is unclear how participants could perform the paired associate memory task with only familiarity information given that foils are always drawn from other experimental items and all stimuli are presented an equal number of times.
Differential medial temporal lobe effects have also been ascribed to memory strength (Squire et al., 2007
). Though we analyzed correct trials only, it is possible that the trend to greater accuracy in the recent condition indicates that subjects held stronger memories during this session. Based on the memory strength interpretation, the weaker memory should have resulted in decreased hippocampal activity and increased perirhinal cortex activity. However, we observed an increase and decrease putatively within the hippocampus. Further the decrease we observed occurred during the delay period and the increase during the visual cue. While differential memory strength remains a possible explanation for some of the observed changes, it cannot account for the full pattern of results. Better spatial resolution within the hippocampus would partially help to address this question, though the memory strength hypothesis does not attempt to address the within trial temporal difference observed.
Task difficulty may also impact the pattern of results in the prefrontal cortex. Again, given the observed trend to decreased sensitivity, recall in the remote condition was likely more difficult. Thus, the increased left prefrontal activity may simply reflect this increased difficulty (Gould et al., 2003
). The additional increase in right prefrontal activity could reflect a change in strategy in response to less vivid memories. Such strategy shifts have been observed for delayed matching tasks with longer delays which presumably also reflect some reduction in vividness (McIntosh et al., 1996
In an attempt to avoid the potentially confounding effects of difficulty, we used a high criterion level during training, excluded subjects who could not accurately learn the pairings quickly, and excluded subjects who could not accurately respond during testing. Furthermore, we examined only correct responses that were given quickly to pairings to which subjects responded correctly during both sessions; incorrect responses were modeled separately and excluded from the analyses here. Thus, the subjects were in essence 100% accurate for the trials actually examined for the all activation effects reported here. While these considerations likely reduced the possible difficulty effects, differences in recall difficulty remains a potential factor influencing the observed findings. Further study using parametric manipulations of difficulty and consolidation should be used to evaluate their independent effects.
A further limitation of the study may arise from the longitudinal design. Contrasting different scanning sessions potentially induces confounds related to uncontrollable changes in subjects and within the scanner itself. Designs where different item pairs trained at different times and tested within a single session would complement the current study. However, several of these confounding effects may be reduced by staggering subject enrolment such that the recent session of one subject occurs after the remote session of another avoiding coherent scanner confounds, removing the main effects of runs (and thus session), correcting for non-sphericity, and examining only correct trials. All of these methods were employed here. In addition, the current design has the advantage of testing the exact same memories, avoiding counter-balancing issues, and avoiding potential interactions between memories from the same category acquired at different times.
Though the opposing consolidation related effects within the medial temporal region observed here may or may not be completely reconcilable with the extended theory, they potentially explain previous contradictory imaging results. Previous human imaging studies of systems level consolidation have identified consolidation-related decreases in the hippocampal complex while others have reported consolidation related increases. Most early studies and even several later studies employed blocked designs where the BOLD signal from multiple temporally adjacent trials (including potentially incorrect trials) is combined to observe effects. Previous event related designs have used short trials and thus were unable to disambiguate differential effects occurring at sub-trial time-scales. A lack of temporal resolution, combined with the limited spatial resolution of fMRI, may account for previous inconsistent results if the two effects observed here became spatio-temporally blurred together in previous analyses. Unfortunately, the BOLD signal measured by fMRI has a lower limit to its temporal resolution that is orders of magnitude above that of neural activity. Elongating that neural activity through longer trials as was done here may alter the nature of that activity and thus alter the resulting fMRI data. For example, increasing the trial length likely increased working memory demands which has been shown to alter hippocampal activity (Hannula and Ranganath 2008
). Further study with imaging methods such as MEG which provide superior temporal resolution may help to test the robustness of the observed difference in the trial subcomponents and clarify the temporal pattern of effects.
The goal of the current experiment was to test the predictions of the extended theory of systems level consolidation in a situation where there would be little theoretical disagreement regarding the predicted outcome. To achieve adequate response accuracy levels, we used a large number of training exposures to the experimental pairs which potentially removed the majority of the autonoetic consciousness or “episodic” quality from these associate memories (Tulving, 1985
). Though it is not possible to integrate the knowledge of these nonlinguistic pairings into the broader semantic knowledge base, the associates memories examined here are best described as semantic-like or semanticized memories rather than episodic memories. Multiple Trace Theory agrees with the standard theory that the hippocampal memory system should be less involved in storage and recall of these memories as they age (Nadel and Moscovitch, 1997
). However, the current study does have strong consequences for the debate between these two theories. Human imaging studies using a prospective memory paradigm to test the predictions of Multiple Trace Theory for presumably purely episodic memories have argued that a hippocampal increase or decrease would respectively provide evidence in favor or against the theory (cf. Bossardt et al, Takashima et al., 2006
; Nadel et al., 2007). In the current study examining associate memories, both relative increases and decreases were observed in the hippocampal complex region though with potentially different spatial foci and a different intra-trial temporal profile. This suggests that definitive evidence for or against either theoretical position may not be obtainable using human functional neuroimaging until the stability, cause, and time course of these relative changes are more fully characterized.