Using advanced multimodal imaging, we demonstrate spatial concordance between fMRI and MEG N400 priming effects within left inferior prefrontal extending into precentral, left posterior superior temporal, left medial temporal, right lateral occipitotemporal, and bilateral ventral occipitotemporal cortex, encompassing much of the lingual and fusiform cortex on the left. We also provide iEEG validation of our MEG/fMRI responses in key regions in multiple patients and reveal co-localization between increased gamma power in iEEG and the fMRI BOLD response. summarizes regions of spatiotemporal concordance associated with repetition priming across all three modalities. As can be seen, these priming patterns were largely characterized by reduced responses to repeated words, suggesting facilitation of word processing that is measurable in the hemodynamic and electromagnetic signals.
Neocortical regions showing significant repetition effects in each modality
Furthermore, fMRI revealed repetition enhancement in which repeated words produced greater responses relative to new words in bilateral dorsolateral prefrontal, precuneus, and inferior parietal/supramarginal cortex. Although the MEG ROI analysis indicates a late (~500–600ms) trend for an O > N effects within these ROIs that exceeded our cluster threshold in the surface maps, the condition contrasts did not reach significance at the ROI level. This may be due to our short trial length (i.e., 600ms), which precluded a complete analysis of the late repetition effects that often persist until 700–800ms (Dale et al., 2000
). This late effect has been referred to as the LPC/P3b and may reflect conscious recollection of the repeated words. This has been described previously in incidental memory tasks with a large number of repetitions (Dale et al., 2000
), presumably because word repetitions become apparent to the participant. In addition, the MEG surface maps reveal significant O vs N differences within left ventral occipitotemporal and bilateral superior temporal clusters between 200–240ms that appear to reflect early, transient enhancements to repeated stimuli, as reported in previous MEG studies of visual word processing (Dhond et al., 2001
; Marinkovic et al., 2003
). Although these N vs O effects were not significant in the ROI analysis during the early time window, inspection of the waveforms reveals a trend toward O > N responses across several ROIs. Evidence for O > N activity within these ROIs was not captured by fMRI and it has been suggested that the transient nature of the early O > N response is not robust enough to overcome the sustained N > O response that dominates the fMRI BOLD response in these same regions (Marinkovic et al., 2003
Correlational analysis between our fMRI and MEG repetition priming effects across individuals revealed that fMRI BOLD suppression correlated with MEG priming effects from 350–450ms, but only within the left inferior prefrontal, left superior temporal, and right occipitotemporal region. Repetition suppression within each of these regions has been reported in previous neuroimaging studies of word and object priming (Marinkovic et al., 2003
; Schacter and Buckner, 1998
). Our within-subject, multimodal fMRI/MEG analysis provides further evidence that these regional priming effects are robust across imaging modalities. Although the relationship between electromagnetic and hemodynamic response changes is complex, a direct correlation between BOLD signal change and N400 modulations has been observed with EEG within the vicinity of the left superior temporal gyrus (Matsumoto et al., 2005
). We extend the literature by demonstrating fMRI-MEG correlations within other perisylvian regions implicated in the N400 effect and by providing validation from iEEG of their local generation.
Recent neuroimaging research has demonstrated that repetition suppression across neocortical regions is unlikely to reflect a unitary process. Rather, there is convincing evidence that repetition priming involves multiple component processes with partially unique anatomical substrates. Whereas early response suppression within bilateral occipitotemporal regions likely reflects a “sharpening” of neural activity in response to the perceptual attributes of the stimulus (Fiebach et al., 2005
; Schacter and Buckner, 1998
) and visual word form priming (Cohen et al., 2002), the late effects (> 300ms) identified in our MEG responses suggest significant top-down influences that may reflect general attention-dependent priming for conceptual information (Klaver et al., 2007
). This top-down interpretation is supported by iEEG ERP and/or high gamma recordings in 5 of 6 patients who showed late N > O responses in left or right occipitotemporal cortex in or near regions showing strong activation in fMRI and MEG. This late N > O effect in occipitotemporal cortex has not been previously reported across all three modalities and provides evidence that priming effects within extrastriate cortex are influenced by both feedforward and feedback mechanisms.
In addition, response suppression within left posterior temporal cortex has been attributed to facilitation of lexical access (Matsumoto et al., 2005
) or recoding of a written word into a lexical representation (Klaver et al., 2007
). This component of repetition priming appears to be independent of the earlier perceptual effects, and may represent automatic, spreading activation of a word s representation. Our data demonstrate response suppression within left temporal cortex in fMRI and in the MEG waveforms that is highly lateralized and sustained after ~250ms. This time period is congruent with other studies that have identified a lexical-processing stage that may represent a transitional stage between perceptual and conceptual priming (Marinkovic et al., 2003
). However, the sustained effects observed in these regions in the MEG surface maps and waveforms indicate that left temporal regions also contribute to the main N400 component of repetition priming.
Response suppression within the left inferior prefrontal region is generally believed to reflect conceptual priming, including a reduced demand for semantic memory retrieval (Wagner et al., 2001
) and/or facilitation of response selection (Thompson-Schill et al., 1997
). Our MEG and fMRI data show response suppression in the left inferior frontal cortex that appears to evolve somewhat latter than the priming effects observed in posterior temporal cortex and is maximal between 350–450ms (i.e., peak N400 effect). The sustained response suppression in left temporal regions during this time supports the notion that left lateral temporal cortex is important for initial lexical access, as well as interactions with prefrontal regions during semantic memory retrieval (Gold and Buckner, 2002
). Inspection of the iEEG waveforms provides evidence of locally-generated N400 responses within the left posterior superior temporal and left inferior prefrontal cortex (i.e., in or near Wernicke’s and Broca’s areas) that support our fMRI and MEG N400 reductions and represent core anatomical substrates of conceptual priming.
Taken together, our data provide evidence that the main repetition priming effects seen in fMRI BOLD responses are those associated with the MEG N400 reductions, and not necessarily with the more transient early or late repetition effects that are apparent in the MEG waveforms. This is consistent with previous findings that iEEG/MEG and BOLD responses correlate reasonably well for the N400, but not as strongly with the scalp P3b/LPC (Halgren, 2004b
). However, our iEEG data did reveal O > N late repetition effects in left dorsolateral prefrontal cortex in all four patients with recordings sampled from this region that peaked between 500–600ms and may reflect LPC/P3b effects. In three patients, the responses were observed in iEEG high gamma responses but not in the ERPs, suggesting that the BOLD effect associated with conscious recollection may be tightly coupled to increased power in the high frequency ranges not always captured with MEG or ERP measurements (Jerbi et al., 2009
; Yuval-Greenberg et al., 2008
The exact relationship between the BOLD response and increased gamma oscillations observed in cognitive tasks in not entirely known, but memory formation has been associated with increased gamma oscillations recorded with iEEG in left temporal and prefrontal regions (Sederberg et al., 2007
). We extend the literature by demonstrating an association between increased gamma power and word priming effects in the context of an incidental memory task. Furthermore, we report increased gamma power for N > O responses in numerous patients in ventral and lateral occipitotemporal, inferior prefrontal, superior temporal, and medial prefrontal cortex that are also reflected in our fMRI activations—many of which were not observed in the ERP data. These findings are consistent with an emerging literature demonstrating that gamma power co-localize with BOLD variations across numerous cortical regions during lexico-semantic tasks (Lachaux et al., 2007
), presumably due to its correlation with local neuronal firing (Manning et al., 2009
In this study, we provide multimodality evidence for the spatiotemporal profile of repetition word priming using fMRI/MEG with support from iEEG recordings. However, there are several limitations to our study that should be noted. First, whereas our MEG and iEEG tasks were event-related, we used a blocked version of the same task for fMRI. A blocked design was selected in order to increase the SNR, optimizing our ability to detect very subtle BOLD changes associated with repetition priming in anterior and ventral temporal lobe regions that are known to be susceptible to signal loss (Chee et al., 2003
; Dale et al., 2000
). Although numerous studies have reported highly similar patterns of activations between blocked and event-related fMRI designs using lexical-semantic tasks (Chee et al., 2003
; Pilgrim et al., 2002
; Wagner et al., 2005
; Weiss et al., 2009
), blocked presentation of items may induce strategies or lead to greater levels of habituation in some regions relative to event-related designs. This may explain the bilateral precuneus and lateral occipitotemporal activations seen in our fMRI data that were not apparent with MEG. Greater BOLD responses to repeated stimuli have been reported previously in bilateral precuneus (Horner and Henson, 2008
)—a region implicated in episodic retrieval (Wagner et al., 2005
) and task difficulty/workload (Korsnes et al., 2008
; Scheibe et al., 2006
). It is unclear in our study whether the fMRI responses observed in this region reflect conscious recollection of previous items or the lower task demands introduced by our blocked presentation. However, the presence of lateral occipitotemporal repetition effects in our iEEG recordings that co-localize with the fMRI activations suggest that task design differences are unlikely to account for the occipitotemporal findings. Although using identical task designs for fMRI and MEG/iEEG would appear ideal, there are possible limitations to this approach as well. Had we implemented an event-related fMRI design, we may have reduced our SNR and failed to detect subtle task effects in the anteriormedial temporal lobe that appear to be involved in repetition priming. Alternatively, we could have designed an event-related fMRI design with a higher number of trials per condition to increase the SNR. However, this would have resulted in a greater number of repetitions in our fMRI task relative to MEG and iEEG tasks. The number of repetitions has been shown to influence priming effects (Ostergaard, 1998
), introducing another confound. Despite task differences, the high spatial correlation across imaging modalities in many critical regions suggests that most of the repetition priming effects were robust to differences in the task design.
Second, we used a very brief SOA (i.e, 600m.s.) in order to increase our SNR by allowing for a large number of averages across task conditions in a relatively short time. This brief SOA diminished our ability to fully evaluate very late MEG repetition effects that generally peak around 600 to 700ms post-stimulus. Finally, it is important to note that iEEG data are acquired from patients who are undergoing evaluation for surgical resection of an epileptic focus. Therefore, many of the iEEG responses were sampled near diseased tissue, and the area sampled in each patient varies and is limited to the details of the electrode placement. These are well-known limitations of iEEG research that cannot be avoided. As is accepted practice in iEEG research (Jerbi et al., 2009
), we sought to minimize the effects of brain pathology in our iEEG responses by eliminating electrodes from which ictal or interictal discharges were recorded. However, it is still possible that one or more of these factors mitigated our ability to record clear N400 or LPC effects in some of the patients or consistently across regions. Nevertheless, we were still able to detect local repetition priming effects with iEEG in one or more patients that supported the temporal and spatial patterns detected with our non-invasive measures. Multimodal imaging data such as these provide unique insight into the timing, location, and spectral features of cognitive processes, such as repetition priming, and demonstrate the validity of using non-invasive measures for understanding complex brain functions.