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Episodic sequence memory is supported by a theta–gamma phase code

Abstract

The meaning we derive from our experiences is not a simple static extraction of the elements but is largely based on the order in which those elements occur. Models propose that sequence encoding is supported by interactions between high- and low-frequency oscillations, such that elements within an experience are represented by neural cell assemblies firing at higher frequencies (gamma) and sequential order is encoded by the specific timing of firing with respect to a lower frequency oscillation (theta). During episodic sequence memory formation in humans, we provide evidence that items in different sequence positions exhibit greater gamma power along distinct phases of a theta oscillation. Furthermore, this segregation is related to successful temporal order memory. Our results provide compelling evidence that memory for order, a core component of an episodic memory, capitalizes on the ubiquitous physiological mechanism of theta–gamma phase–amplitude coupling.

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Figure 1: Theta–gamma model fitting analysis.
Figure 2: Phase analysis of theta–gamma coupling during sequence encoding, plotted by position and subsequent temporal order memory for left posterior cluster of sensors.
Figure 3: Relative biases in gamma power over theta phase by sequence position and subsequent memory.

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Acknowledgements

We thank L. Lohnas and G. Cogan for critical discussions and readings of the manuscript; J. Walker for technical support during MEG recording; S. Haegens for advice and discussion regarding the source localization; and A. Flinker and K. Doelling for critical discussions around methodological considerations and statistical approaches. We'd also like to thank our financial supporters, NIMH grant RO1–MH074692 to L.D.

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Contributions

A.C.H., D.P., Y.E. and L.D. designed the experiment. A.C.H. collected the data. A.C.H. analyzed the data. A.C.H., D.P., Y.E. and L.D. wrote the paper.

Corresponding authors

Correspondence to Andrew C Heusser or Lila Davachi.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Time–frequency power spectrogram during stimulus presentation

A) Average time-frequency spectrogram is plotted across all sensors and all subjects, where 0 represents stimulus onset. Power is calculated relative to a pre-stimulus baseline (-1 to -.5). The line plots on the left side are group-level t-values representing the statistical contrast of the stimulus on period versus the pre-stimulus baseline. The black line represents 0-500ms and the blue line represents 0-2500ms (i.e. the duration of the stimulus on period). B) Time-frequency power is plotted specifically for the two clusters of sensors that showed the pattern of decreasing theta-gamma coupling by sequence position. C) Topographic plots in time bins of 500ms during stimulus presentation. The top row is theta power and the bottom row is gamma power.

Supplementary Figure 2 Theta–gamma coupling topography

Left. Topographic plot of group-level t-statistics representing sensors that showed significant theta-gamma coupling during the sequence encoding task (0-2.5 seconds; thresholded at t(16)>3.96, p<.001). Filled circles on the topographic plot represent significant sensors. Right. Gamma power binned by theta phase for sensors that showed significant theta-gamma coupling. Error bars represent standard error of the group mean. The dotted lines represent the standard error of the mean of the permuted coupling scores (see Methods for details).

Supplementary Figure 3 Power and coupling averaged across significant clusters of sensors

A) Bar graph representing magnitude of theta-gamma coupling (MI or ‘modulation index’) by sequence position averaged across sensors that displayed a significant fit to theta-gamma model. B) Theta power by sequence position averaged across sensors displaying significant fit to theta-gamma model. C) Gamma power by sequence position averaged across sensors displaying significant fit to theta-gamma model. Error bars represent standard error of the mean.

Supplementary Figure 4 Unthresholded theta–gamma model fit data and power control analysis

The left topographic plot is a statistical plot representing the fit of the theta-gamma model prediction to the theta-gamma coupling data prior to applying the cluster threshold (i.e. Figure 1d before cluster correction, See Methods for details of cluster size permutation procedure). The right topographic plot represents the result of an analysis where power effects in the theta and gamma band were first regressed out of the theta-gamma coupling data and then the residuals of this analysis were fit to the predicted pattern from the theta-gamma model.

Supplementary Figure 5 Source localization analysis with various statistical thresholds

The statistical maps represent the group-level fit of the decreasing PAC by sequence position model to the theta-gamma coupling data at various thresholds (p<.001,.01.1, all uncorrected). Coronal slices are on the top row, axial slices in the middle row, and sagittal slices are along the bottom row.

Supplementary Figure 6 Group-averaged gamma power binned by theta phase for significant clusters

On the left, data was extracted from the left posterior cluster of sensors that significantly fit the model of decreasing phase amplitude coupling. On the top is the group-average across all trials (i.e. irrespective of sequence position). In the middle, theta-gamma coupling is plotted as a function of sequence position only for trials where the order was later correct and on the bottom, only for trials where the order was later incorrect. The plots on the right are the same as the left, but for the left lateral cluster of interest.

Supplementary Figure 7 Gamma power (70–100 Hz) during stimulus presentation

A) Group-averaged time course of gamma power (-.5 to 2.5 seconds) in left posterior cluster of interest for early (dark gray; sequence positions 1&2), middle (blue; 3&4) and later (yellow; 5&6) sequence positions. B) Same as A but for only correctly remembered sequences. C) Same as A but only for incorrect sequences. Error bars represent standard error of the mean.

Supplementary Figure 8 Theta phase locking (3–8 Hz) during stimulus presentation

A) Group-averaged time course of theta phase locking (-.5 to 2.5 seconds) in left posterior cluster of interest for early (dark gray; sequence positions 1&2), middle (blue; 3&4) and later (yellow; 5&6) sequence positions. B) Same as A but for only correctly remembered sequences. C) Same as A but only for incorrect sequences. Error bars represent standard error of the mean.

Supplementary Figure 9 Average theta–gamma model fit statistic with and without first 500 ms

The bar on the left represents the average model fit for the original analysis on the entire stimulus presentation (0-2500ms), averaging over sensors that showed a significant group-level model fit. The bar on the right represents the average model fit for the new analysis where we remove the first 500ms (500-2500ms), eliminating the possible contribution of the evoked response. Error bars represent standard error of the mean. *** p<.001.

Supplementary Figure 10 Theta phase coding after removing first 500 ms

A) Distribution of gamma power over theta phase by sequence position bin for only correctly remembered sequences (Watson William’s Test F(5,96)=9.10, p=1.05e-5). B) Distribution of gamma power over theta phase by sequence position bin for incorrectly remembered sequences (Watson William’s Test F(5,96)=6.42, p=2.5e-2). Sequence by position interaction is significant (Harrison-Kanji Test: F(5,196)=11.03, p=.025). C) Group-level statistics for theta phase coding effect with (solid line) and without first 500ms (dashed line). Error bars represent standard error of the mean. *p<.05

Supplementary Figure 11 Theta-gamma coupling during intertrial interval

(A) Histogram of gamma power over theta phase for the stimulus presentation interval (dark blue) and the ITI (light blue). (B) Decreasing PAC by sequence position model fits during the entire stimulus interval, after removing the first 500ms and during the ITI. (C) Distribution of gamma power over theta by sequence position for correct order sequences during the ITI (Watson William’s Test: F(5,96)=9.10, p=1.07e-5). (D) Distribution of gamma power over theta by sequence position for incorrect sequences during the ITI (Watson-Williams Test: F(5,96)=9.09, p=4.03e-4). Sequence by position interaction trending (Harrison-Kanji Test: F(5,196)=8.02, p=.07). Error bars represent standard error of the mean. ~ p<.1, * p<.05, ** p<.01, *** p<.001.

Supplementary Figure 12 Testing for systematic theta phase shift by sequence position

The top row is simulated data in the theta frequency for each sequence position, where we simulated a systematic linear phase shift over the sequence. The bottom row is the group-averaged data after computing each of these metrics within-subject. The left column is the data filtered in the theta band. The right row is the lag of the peak in the pair-wise cross-correlation. If a systematic phase shift was present in the data, we would expect a monotonically increasing lag as a function of sequence position. Error bars represent standard error of the mean.

Supplementary Figure 13 Theta (3–8 Hz) phase symmetry by sequence position

(A) On the left is a simulated 4 Hz sine wave. Plotted in the middle is the phase time series of the theta wave. On the right, the waveform is plotted in polar coordinates, where the circular angle represents the phase and the distance from the center represents the power. (B) The same plot as listed above, but for a square wave at 4 Hz. (C) Polar plot representing the grand average of the MEG time series during stimulus presentation (0 to 2.5s) filtered in the theta range (3-8 Hz) and averaged over the left posterior cluster of sensors. Each color represents a distinct sequence position.

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Heusser, A., Poeppel, D., Ezzyat, Y. et al. Episodic sequence memory is supported by a theta–gamma phase code. Nat Neurosci 19, 1374–1380 (2016). https://doi.org/10.1038/nn.4374

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