The human brain is adept at anticipating upcoming events, but in a rapidly changing world, it is essential to detect and encode events that violate these expectancies. Unexpected events are more likely to be remembered than predictable events, but the underlying neural mechanisms for these effects remain unclear. We report intracranial EEG recordings from the hippocampus of epilepsy patients, and from the nucleus accumbens of depression patients. We found that unexpected stimuli enhance an early (187 ms) and a late (482 ms) hippocampal potential, and that the late potential is associated with successful memory encoding for these stimuli. Recordings from the nucleus accumbens revealed a late potential (peak at 475 ms), which increases in magnitude during unexpected items, but no subsequent memory effect and no early component. These results are consistent with the hypothesis that activity in a loop involving the hippocampus and the nucleus accumbens promotes encoding of unexpected events.

We examined the effect of unpredicted events on memory by using a version of the “Von Restorff” paradigm () in which participants studied pictures of faces and houses shown in grayscale against a red or green background ( Figure 1 ). While the majority of items came from one category (“expected items;” e.g., faces on a red background), a small proportion of interleaved stimuli came from the other category (“unexpected items;” e.g., houses on a green background) in a balanced design (see Supplemental Information ). Participants were subsequently tested on memory for the expected and unexpected items from each list, allowing us to examine encoding activity as a function of subsequent memory performance.

The paradigm included a Study Phase (encoding of items, top) and a Test Phase (retrieval, bottom). In both phases, a majority of items belonged to one category with respect to background color and content (expected items; e.g., red faces), while a minority of items were deviant (unexpected items; e.g., green houses). See also Table S1 for behavioral data.

Here, we report results of intracranial electroencephalography (EEG) studies aimed at clarifying the relationship between novelty processing and memory formation in the hippocampus and nucleus accumbens. Two groups of patients participated in this study: one group of eight patients with medication-resistant epilepsy had electrodes implanted in the hippocampus in order to localize the seizure foci. Another group of six patients had electrodes implanted in the nucleus accumbens for an experimental trial of deep brain stimulation for medically intractable depression (). More details about the participants are provided in the Supplemental Information , available online.

A critical function of the human brain is to extract patterns from recent events in order to generate predictions about the future (). Violations of such predictions activate a distributed network involved in orienting to and encoding novel events, thereby resulting in enhanced memory formation (). According to one model based on animal studies, the hippocampus may initially compute a novelty signal (as the difference between a predicted stimulus and an actual stimulus), which is propagated to the nucleus accumbens (). The nucleus accumbens—in close interaction with the dopaminergic midbrain (e.g.,)—is thought to relay information about expectancy, salience, and goal information, thereby influencing dopaminergic modulation of hippocampal long-term potentiation and encoding of unexpected stimuli or events (). This model predicts two neural signatures of expectancy in the hippocampus, an earlier and a later one; the later one should be associated with enhanced memory for unexpected items. Furthermore, it predicts that an expectancy signal is computed in the hippocampus first and then transferred to the nucleus accumbens. These predictions on the temporal order in which novelty and memory are computed in different brain structures remain to be tested, however.

Second, we calculated single-trial amplitude covariance between activity in epilepsy and depression patients. Our reasoning for this relatively unusual measure of between-subject amplitude correlation was that the specific temporal pattern of expected and unexpected items would induce systematic fluctuations of EEG amplitudes—e.g., related to primacy, recency, and temporal variations of expectations (). These fluctuations should be visible both in the hippocampus and in the nucleus accumbens, because in each patient, identical sequences of items were presented in corresponding blocks. We thus calculated correlations across trials for all pairs of hippocampal and nucleus accumbens patients. Only corresponding trials which were free of artifacts in both patients of each pair were analyzed. Again, we predicted that hippocampal activity between 150 and 250 ms should be maximally correlated with nucleus accumbens activity around 300 ms later. Figure 4 C shows that we observed a peak correlation at a latency of around 300–400 ms. In all but one pair, correlation values (calculated as for the within-subject analysis) were significant (mean R: 0.206; range: 0.169–0.303; range of p values: 0.0001–0.047).

The data presented thus far only provide indirect evidence for hippocampal-accumbens information transfer, because the nucleus accumbens and hippocampal ERPs were recorded in separate patient groups. However, two additional analyses were conducted to assess functional connectivity in our data. First, we used data from two epilepsy patients who were implanted not only with hippocampal depth electrodes, but also with extensive subdural strip and grid electrodes (>100 electrode contacts; see Figure S2 ), to conduct a source analysis of activity within the nucleus accumbens (; see Supplemental Experimental Procedures ). In this analysis, nucleus accumbens activity was estimated using activity from subdural grid and strip electrodes (not from hippocampal depth electrodes) as input. In both patients, the reconstructed time courses of activity within the nucleus accumbens were qualitatively very similar to the time courses of nucleus accumbens activity measured in the depression patients ( Figure 4 A ). Unexpected items elicited larger components in the same time window as for the measured data. In these two patients, we calculated functional connectivity between the (measured) hippocampal activity and the (reconstructed) nucleus accumbens activity. The hypothesis that unexpected information is detected in the hippocampus and transferred to the nucleus accumbens predicts that activity around the early hippocampal component (peaking at 187 ms) is correlated with the later component in the nucleus accumbens (with a peak at 475 ms). Thus, hippocampal activity at around 150–250 ms should correlate with activity around 300 ms later in the nucleus accumbens. We thus calculated cross-correlations across trials (i.e., single-trial amplitude covariance; e.g.,) for hippocampal activity around the early component (between 150 and 250 ms) with all time points in the nucleus accumbens. Next, for each of these hippocampal time points, we searched for the nucleus accumbens time point with the maximal correlation value. Figure 4 B depicts the latency between hippocampal and nucleus accumbens time points with maximal correlation. In both patients, we found that hippocampal activity in this time window correlated highest with nucleus accumbens activity 200–400 ms later, consistent with the predicted lag of 300 ms. Notably, latencies were relatively constant across several tens of milliseconds in this time interval (see the plateaus of latency values), indicating that contiguous amplitude values in the hippocampus are maximally correlated with contiguous amplitude values in the nucleus accumbens. To assess the significance of this correlation, we calculated average correlation values during this plateau—i.e., averaged across all points in time between 150 and 250 ms when latencies were between 200 and 400 ms. Indeed, we found a significant correlation in this range in both patients (patient 1: R = 0.183; t= 3.05; p < 0.005; patient 2: R = 0.1251; t= 2.106; p < 0.05).

See also Figure S2 for implantation schemes of the two patients with reconstructed nucleus accumbens activity.

(B) Latency of (estimated) nucleus accumbens activity with maximal cross-correlation to (recorded) hippocampal activity around the peak of the early novelty response in the hippocampus.

To further explore the neural signature underlying processing of unexpected items, we conducted time-frequency analyses of activity within the hippocampus and nucleus accumbens. As shown in Figure 3 A , the most pronounced difference between processing of unexpected and expected items in the hippocampus was an early (200–400 ms) increase and later (500–1400 ms) decrease of theta band activity, and an increase between 500–700 ms and 1000–1100 ms in the high gamma (70–90 Hz) frequency range (statistical analyses are described in the Supplemental Results ).

(A) Theta (3–8 Hz) power is first (200–400 ms) increased and later (500–1400 ms) decreased during processing of unexpected as compared with expected items in the hippocampus. Higher (70–90 Hz) gamma power is selectively increased in the hippocampus during processing of unexpected items between 500–700 and 1000–1100 ms. The color bar applies to all power plots.

As noted above, some models suggest that the late-onset expectancy effects in the hippocampus might be modulated by a saliency signal conveyed by the nucleus accumbens (). We therefore investigated electrophysiological correlates of expectancy processing in the patients with electrodes in this region. Visual inspection of the EEG traces recorded within the nucleus accumbens revealed a negative deflection with a latency of 475.2 ± 177.2 ms (mean ± SEM; Figure 2 B). This ERP component was significantly larger for unexpected compared with expected items (t= 3.82; p < 0.05). A two-way ANOVA on this component revealed no main effect of memory (F= 0.171; p > 0.6) and no interaction (F= 0.274; p > 0.6). Furthermore, no early potential as in the hippocampus became apparent, and statistical comparison of expected and unexpected trials in the same window as in the hippocampus did not reveal a difference (t= 0.52; p > 0.5).

Event-related potentials (ERPs) recorded from the hippocampus revealed an early positive peak at 186.9 ± 16.7 ms (mean ± SEM) and a later negative peak at 481.5 ± 63.3 ms, which resembled the hippocampal P300 potential (). Both components were significantly larger during processing of unexpected as compared with expected stimuli (early component: t= 2.64; p < 0.05; late component: t= 3.91; p < 0.01; Figure 2 A ). Effects of repeat items are shown in Figure S1 . Moreover, a two-way ANOVA for the late component with “expectancy” and “memory” as repeated-measures revealed a significant main effect of expectancy (F= 9.64; p < 0.05) and a highly significant expectancy × memory interaction (F= 12.92; p < 0.01), but no main effect of memory (F= 3.31; p > 0.1). Subsequent two-tailed t tests revealed an increased late potential during encoding of subsequently remembered as compared with forgotten unexpected items (t= 2.72; p < 0.05), but no subsequent memory effect for expected items (t= 0.07; p > 0.9). A similar analysis on the early component revealed no significant effect of memory (F= 3.45, p > 0.1) and no expectancy × memory interaction (F= 1.07, p > 0.1).

(B) (Left) Image acquired during MRI-guided stereotactic implantation of bilateral electrodes for deep brain stimulation in the nucleus accumbens of depression patients. (Bi) Expectancy effect on the nucleus accumbens ERPs. (Bii and Biii) No effect of subsequent memory as in the hippocampus became apparent.

(A) ERPs from the hippocampus. (Left) Postimplantation MRI of an epilepsy patient implanted with bilateral depth electrodes in the hippocampus. (Ai–Aiii) Hippocampal ERPs during processing of items of different types in the Study Phase. (Ai) Enhancement of hippocampal early and late ERP components during processing of unexpected as compared with expected items. (Aii and Aiii) The late ERP component in the hippocampus reflects the interaction of expectancy and subsequent memory.

Corrected recognition scores (confident hits minus false alarms) in epilepsy patients were significantly better for unexpected than for expected items (29.9 ± 6.7 versus 20.5% ± 4.3%; t= 2.49; p < 0.05). This difference was in the same direction in the group of depression patients, although it was not statistically significant (25.9% ± 5.4% versus 22.2% ± 4.6%; t= 0.54; p = 0.66). The nonsignificant Von Restorff effect in depression patients is probably due to the relatively low sample size (see Supplemental Information for further information). Moreover, a two-way ANOVA revealed that performance in the two groups was not significantly different (F= 0.03; p = 0.87), and that there was no interaction between group and unexpected versus expected items (F= 0.475; p = 0.5) (for details, see Table S1 , available online). In both groups, reaction times during encoding (i.e., related to the pleasant/unpleasant rating of items) were significantly slower for unexpected than expected items (epilepsy patients: t= 3.88; p < 0.01; depression patients: t= 2.98; p < 0.05), suggesting that expectancy was processed similarly.

Discussion

Lisman and Grace (2005) Lisman J.E.

Grace A.A. The hippocampal-VTA loop: controlling the entry of information into long-term memory. Our findings show that it is possible to estimate the relative sequence of processes in the human hippocampus and nucleus accumbens: whereas the early hippocampal and the (later) nucleus accumbens components were modulated only by expectancy, the late hippocampal component was correlated with both expectancy and subsequent memory, and likely reflects the interaction of these processes. Thus, our data are in close agreement with the model by. They are consistent with the idea that hippocampal activity may initially signal the occurrence of an unexpected event, and that the nucleus accumbens may influence subsequent hippocampal processing, which serves to promote memory encoding.

Fernández et al. (1999) Fernández G.

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Elger C.E. Real-time tracking of memory formation in the human rhinal cortex and hippocampus. Yonelinas, 2001 Yonelinas A.P. Components of episodic memory: the contribution of recollection and familiarity. In a previous study using a word-list learning paradigm,found subsequent memory effects on late positive potentials in the hippocampus. These effects were not observed in the current study, possibly due to differences in task characteristics and material: first, no manipulation of expectancy was conducted in the Fernández study; second, words instead of pictorial stimuli were used; finally, free recall was tested in the study by Fernández and colleagues, which depends on conscious access to a memory trace, whereas we measured recognition memory. The latter difference might be particularly important because recognition memory in our study may rely on both stimulus familiarity and conscious recollection ().

Fell et al., 2004 Fell J.

Dietl T.

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Fernández G. Neural bases of cognitive ERPs: more than phase reset. Buzsáki, 2002 Buzsáki G. Theta oscillations in the hippocampus. Supplementary time-frequency analyses demonstrated a role for hippocampal theta and high gamma oscillations in processing of unexpected information. The initial increase and subsequent decrease in hippocampal theta for unexpected events are possibly related to the late hippocampal component, which has a frequency composition in the delta/theta band. Indeed, a previous intracranial EEG study using an oddball paradigm showed that the hippocampal P300 component was associated with an early (200–500 ms) increase and a later (500–1000 ms) decrease in theta power (), very similar to the results from our current study. Hippocampal theta activity in rats depends on at least two different generators (reviewed in). Inputs from the entorhinal cortex induce theta oscillations that persist after antagonism to muscarinergic acetylcholine. In contrast, projections from the medial band of broca and septum cause a tonic cholinergic excitation and phasic GABAergic inhibition of hippocampal basket cells, which induce rhythmic inhibitory postsynaptic potentials in the theta frequency range on their target pyramidal cells in the CA1 region.

Fuchs et al., 2007 Fuchs M.

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Kastner J. Development of volume conductor and source models to localize epileptic foci. One limitation of our study is that nucleus accumbens and hippocampal activity were recorded in two different groups of subjects, and therefore the data only provide an indirect measure of functional connectivity between these brain regions. This is a necessity, however, because the location of electrode placements in human patients must be dictated solely by clinical considerations, and to our knowledge, there are no conditions that would require electrode placement in both hippocampus and nucleus accumbens. To indirectly address the idea that novelty information is transferred from the hippocampus to the nucleus accumbens, we calculated cross-correlations between hippocampal amplitudes around the time of the early potential with estimated nucleus accumbens time courses (in the same patients) and measured activity in the depression patients. Results from both analyses are consistent with the proposed information transfer from the hippocampus to the nucleus accumbens, but correlations between the nucleus accumbens component and the late hippocampal potential were less clear (see Supplemental Information ). However, it should be noted that both measures have their limitations. Time courses in the nucleus accumbens were estimated using anatomically defined regions of interest in patients with extensive implantation schemes. Although source analyses based on intracranial EEG data are most likely more accurate than source reconstruction based on surface EEG because they avoid the spatial low-pass filter properties of the skin and bone (e.g.,), reconstruction of activity from deep brain structures is notoriously difficult. The estimated time courses in the nucleus accumbens resembled those that were recorded in depression patients; however, a validation of this analysis in animals with both subdural and nucleus accumbens electrodes would be useful. Our second analysis—correlation of amplitudes between subjects relying on joint intertrial variability across the experiment—is complicated by the variability of single-trial responses between subjects. Again, it would be necessary to test this approach in animals with electrodes in both regions.

In summary, whereas the early hippocampal and the later nucleus accumbens components were modulated only by expectancy, the late hippocampal component was modulated by both expectancy and subsequent memory. We suggest that this later process reflects the interaction of novelty signaling and memory encoding. Taken together, these results speak to the relative timing of expectation effects in different regions of the human brain, and they support models of accumbens-hippocampus interactions during encoding of unexpected events.