. 2024 Jan 3;15(1):215.

doi: 10.1038/s41467-023-44295-8.

Awake ripples enhance emotional memory encoding in the human brain

Haoxin Zhang^#^{1

2}, Ivan Skelin^#^{3

4}, Shiting Ma⁵, Michelle Paff⁶, Lilit Mnatsakanyan⁵, Michael A Yassa^{5

7

8}, Robert T Knight^{9

10}, Jack J Lin^{11

12}

Affiliations

¹ Department of Neurology, University of California Irvine, Irvine, 92603, CA, USA. haoxinz1@uci.edu.
² Department of Biomedical Engineering, University of California Irvine, Irvine, 92603, CA, USA. haoxinz1@uci.edu.
³ Krembil Brain Institute, Toronto Western Hospital, Toronto, Ontario, M5T 1M8, Canada.
⁴ Department Center for Advancing Neurotechnological Innovation to Application, Toronto, Ontario, M5G 2A2, Canada.
⁵ Department of Neurology, University of California Irvine, Irvine, 92603, CA, USA.
⁶ Department of Neurosurgery, University of California Irvine, Irvine, 92603, CA, USA.
⁷ Department of Neurobiology and Behavior, University of California Irvine, Irvine, 92697, CA, USA.
⁸ Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, 92697, CA, USA.
⁹ Department of Psychology, University of California Berkeley, Berkeley, 94720, CA, USA.
¹⁰ Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, 94720, CA, USA.
¹¹ Department of Neurology, School of Medicine, University of California Davis, Sacramento, 95817, CA, USA. jajlin@ucdavis.edu.
¹² Center for Mind and Brain, University of California Davis, Davis, 95618, CA, USA. jajlin@ucdavis.edu.

^# Contributed equally.

PMID: 38172140
PMCID: PMC10764865
DOI: 10.1038/s41467-023-44295-8

Awake ripples enhance emotional memory encoding in the human brain

Haoxin Zhang et al. Nat Commun. 2024.

. 2024 Jan 3;15(1):215.

doi: 10.1038/s41467-023-44295-8.

Authors

Haoxin Zhang^#^{1

2}, Ivan Skelin^#^{3

4}, Shiting Ma⁵, Michelle Paff⁶, Lilit Mnatsakanyan⁵, Michael A Yassa^{5

7

8}, Robert T Knight^{9

10}, Jack J Lin^{11

12}

Affiliations

¹ Department of Neurology, University of California Irvine, Irvine, 92603, CA, USA. haoxinz1@uci.edu.
² Department of Biomedical Engineering, University of California Irvine, Irvine, 92603, CA, USA. haoxinz1@uci.edu.
³ Krembil Brain Institute, Toronto Western Hospital, Toronto, Ontario, M5T 1M8, Canada.
⁴ Department Center for Advancing Neurotechnological Innovation to Application, Toronto, Ontario, M5G 2A2, Canada.
⁵ Department of Neurology, University of California Irvine, Irvine, 92603, CA, USA.
⁶ Department of Neurosurgery, University of California Irvine, Irvine, 92603, CA, USA.
⁷ Department of Neurobiology and Behavior, University of California Irvine, Irvine, 92697, CA, USA.
⁸ Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, 92697, CA, USA.
⁹ Department of Psychology, University of California Berkeley, Berkeley, 94720, CA, USA.
¹⁰ Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, 94720, CA, USA.
¹¹ Department of Neurology, School of Medicine, University of California Davis, Sacramento, 95817, CA, USA. jajlin@ucdavis.edu.
¹² Center for Mind and Brain, University of California Davis, Davis, 95618, CA, USA. jajlin@ucdavis.edu.

^# Contributed equally.

PMID: 38172140
PMCID: PMC10764865
DOI: 10.1038/s41467-023-44295-8

Abstract

Enhanced memory for emotional experiences is hypothesized to depend on amygdala-hippocampal interactions during memory consolidation. Here we show using intracranial recordings from the human amygdala and the hippocampus during an emotional memory encoding and discrimination task increased awake ripples after encoding of emotional, compared to neutrally-valenced stimuli. Further, post-encoding ripple-locked stimulus similarity is predictive of later memory discrimination. Ripple-locked stimulus similarity appears earlier in the amygdala than in hippocampus and mutual information analysis confirms amygdala influence on hippocampal activity. Finally, the joint ripple-locked stimulus similarity in the amygdala and hippocampus is predictive of correct memory discrimination. These findings provide electrophysiological evidence that post-encoding ripples enhance memory for emotional events.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Memory discrimination is more accurate for emotional stimuli.**
a Task structure: participants are presented with an image (Stimulus encoding). Following presentation, they rate the valence of the image as negative, neutral, or positive (Post-Encoding/Response). Once all images are presented and rated, participants are presented with 3 types of stimuli - Repeat (identical), Lure (slightly different) or Novel (stimuli not seen during encoding) - and classify each stimulus as Old or New. b Correct discrimination is highest for Novel stimuli (93.9 ± 1.4%; median ± SEM), followed by Repeats (89.4 ± 2.4%) and Lures (61.5 ± 3.7%). Two-sided paired t-test: Novel vs. Repeat, *t(6) = 3.33, p = 0.016; Novel vs. Lure, ***t(6) = 8.36, p = 0.0002; Repeat vs. Lure, *** t(6) = 6.13, p = 0.0009. c Correct discrimination of Lure stimuli is positively associated with encoded stimulus-induced arousal (*t(452) = 1.98, p = 0.047, β = 0.3 ± 0.12, two-sided logistic linear mixed-effect model) and valence (t(452) = 1.48, p = 0.137, β = 0.15 ± 0.09, n_participants = 7, two-sided logistic linear mixed-effect model), while negatively associated with lure pair similarity (*t(452) = −2.06, p = 0.039, β = −0.24 ± 0.00, n_participants = 7, two-sided logistic linear mixed-effect model). The beta sign and magnitude indicate effect direction and strength, respectively. Dots correspond to individual participants. Box and bar indicate mean and 95% CI. d Probability of correct Lure discrimination as a function of lure pair similarity and stimulus-induced arousal. The solid line shows the actual proportion of New responses (y-axis) as a function of Lure stimulus SI (x-axis) for low arousal (blue) or high arousal stimuli (red). The low/high arousal groups were created using the median split. Source data are provided as a Source Data file.

**Fig. 2. The post-encoding ripple rate predicts the stimulus-induced arousal and memory discrimination.**
a Reconstructed locations of hippocampal (blue) and amygdala electrodes (red). b The ripple grand average waveform (n = 4689 ripples in 6 hippocampal channels, 6 participants). Line and shaded areas represent the mean ± SEM. c The ripple rate (events/sec) is significantly higher following encoding of arousing (top right; *z(5) = −2.0, p = 0.046, Two-sided Wilcoxon signed-rank test) and later correctly discriminated stimuli (bottom right, *z(5) = −2.2, p = 0.028, Two-sided Wilcoxon signed-rank test). The ripple rate was showing no conditional differences during stimulus encoding (left column, n.s. as non-significant, p’s > 0.05, Benjamini-Hochberg correction for multiple comparisons). Box and bar indicate mean ± SEM. Source data are provided as a Source Data file.

**Fig. 3. Post-encoding stimulus similarity in the hippocampus and amygdala around ripple.**
a Ripple-locked similarity in the amygdala (top) and hippocampus (bottom) during the post-encoding period (line and shaded areas represent the mean ± SEM). b Post-encoding stimulus similarity is greatest around the time of ripples as shown by comparison with the null-distribution (within ± 250 msec). Shaded areas denote the null-distribution 95% confidence interval. Similarity in the hippocampus overlaps with ripple peak (orange), while similarity in the amygdala peaks prior to and after the ripples (magenta). c Ripple-locked post-encoding stimulus similarity in the amygdala is significantly higher for arousing stimuli (top left, p = 0.035, see Methods; two-sided non-parametric cluster-based permutation test) but is not associated with subsequent discrimination (bottom left, n.s. as non-significant, p = 0.066). Ripple-locked post-encoding stimulus similarity in the hippocampus is significantly higher for correctly discriminated Lure stimuli (bottom right, p = 0.008, see Methods; two-sided non-parametric cluster-based permutation test) but does not depend on stimulus-induced arousal (top right, n.s. as non-significant, p > 0.1). Line and shaded areas represent the mean ± SEM. d Double-dissociation between the post-encoding ripple-locked stimulus representation in hippocampus and amygdala. Left: The association between the stimulus arousal and post-encoding ripple-locked stimulus similarity was stronger in the amygdala (−70 to 20 msec relative to ripple peak, p < 0.001, one-sided non-parametric cluster-based permutation test). Right: The association between the later correct Lure discrimination and post-encoding ripple-locked stimulus similarity was stronger in the hippocampus (−60 to 10 msec relative to ripple peak, p = 0.046, one-sided non-parametric cluster-based permutation test). The line and shaded areas represent the mean ± SEM of the individual participant t-values. Source data are provided as a Source Data file.

**Fig. 4. Synchronously increased ripple-locked post-encoding stimulus similarity in the hippocampus and amygdala predicts the correct Lure discrimination.**
a The ripple-locked joint stimulus similarity in the hippocampus and amygdala for the correct (left) and incorrect (right) discrimination trials. Significant similarity in the amygdala starts 100 msec prior to the ripple peak, followed by the hippocampus (−50 to 200 msec). There is no significant joint stimulus similarity during incorrect Lure discrimination trials, suggesting that the cross-structure joint stimulus similarity may be required for correct Lure discrimination. b Mutual information (abbreviated as MI) difference for the amygdala (abbreviated as AMY) and hippocampal (abbreviated as HPC) stimulus similarity time-courses, during the post-encoding ripple windows (correct Lure discrimination - top, incorrect Lure discrimination - bottom). Positive values denote stronger amygdala to hippocampus (AMY → HPC) directionality. A temporal cluster of significant MI difference (AMY → HPC) is present before ripple peak time (−70 to −30 msec) after encoding of correctly discriminated Lure stimuli (top; p = 0.038, see Methods), indicating that hippocampal stimulus similarity is better predictable by amygdala stimulus similarity than vice versa. This effect is present only during the post-encoding period for correctly discriminated Lure stimuli (left), but not for the incorrectly discriminated Lure stimuli (right, n.s. as non-significant). The line and shaded areas represent the mean ± SEM of the individual participant MI difference. Source data are provided as a Source Data file.

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Awake ripples enhance emotional memory encoding in the human brain

Affiliations

Awake ripples enhance emotional memory encoding in the human brain

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