Slow-Theta-to-Gamma Phase-Amplitude Coupling in Human Hippocampus Supports the Formation of New Episodic Memories

Abstract

Phase-amplitude coupling (PAC) has been proposed as a neural mechanism for coordinating information processing across brain regions. Here we sought to characterize PAC in the human hippocampus, and in temporal and frontal cortices, during the formation of new episodic memories. Intracranial recordings taken as 56 neurosurgical patients studied and recalled lists of words revealed significant hippocampal PAC, with slow-theta activity (2.5-5 Hz) modulating gamma band activity (34-130 Hz). Furthermore, a significant number of hippocampal electrodes exhibited greater PAC during successful than unsuccessful encoding, with the gamma activity at these sites coupled to the trough of the slow-theta oscillation. These same conditions facilitate LTP in animal models, providing a possible mechanism of action for this effect in human memory. Uniquely in the hippocampus, phase preference during item encoding exhibited a biphasic pattern. Overall, our findings help translate between the patterns identified during basic memory tasks in animals and those present during complex human memory encoding. We discuss the unique properties of human hippocampal PAC and how our findings relate to influential theories of information processing based on theta-gamma interactions.

Keywords: episodic memory; hippocampus; phase–amplitude coupling; theta.

Figure 1.

Summary of the Free Recall task and the distribution of cortical electrodes in our dataset. (A) Timeline of a single trial in Free Recall task. The time bin from 400 ms following the onset of the memory item through 1800 ms was used for analysis. (B) Example of all trials completed by a single participant across 4 sessions. The serial position of correct recall items is shown, along with the timing of item retrieval following the onset of the recall cue. (C) Brain plot showing the number of participants with electrodes located in each portion of the neocortex. All 56 participants included in the analysis had at least 1 hippocampal electrode.

Figure 2.

Identification of phase–amplitude coupling (PAC). (A) Mean normalized power values across 10 phase bins for a single frequency (modulating phase)–frequency (modulated amplitude) step. This same analysis was performed at each step in the spectrum. (B) Summary graph for all frequency–frequency steps showing the P-value at each step from the permutation procedure detecting significant PAC. Left and center plots show a concentration of effect in the slow-theta band (for gamma modulation) while the plot in right-hand column shows 4–9 Hz theta modulation of gamma band power. Circle indicates the ${\varphi }_{f1}-A_{f2}$ pair from which the binned power values (shown in the top row) were drawn. (C) Preferred phase for PAC as determined by circular regression. Phase values for frequency–frequency pairs with significant PAC are plotted. Preferred phase is conserved across significant pairs within the frequency band.

Figure 3.

Phase–amplitude coupling aggregated across all recordings. (A) Histograms compiling total number of electrodes exhibiting significant PAC in each brain location during item encoding. For the hippocampus, high and low gamma amplitude is most strongly modulated by slow-theta phase while, in the temporal and frontal cortex, low gamma amplitude is preferentially modulated by 4–9 Hz theta phase. Color scale is a percentage of all electrodes in each brain area exhibiting significant PAC. Inset roseplots are histograms compiling the preferred phase for low gamma band modulation by slow-theta (bottom) and 4–9 Hz theta (top) phase as a percentage of all the electrodes in each brain area. For hippocampal slow theta, preferred phase exhibits a bimodal pattern with a concentration at ∼70° and again at ∼180°. Four- to nine-Hertz theta phase in the temporal and frontal cortex is strongly clustered at 180°. (B) Normalized effect size at each frequency for gamma band PAC. The effect for the hippocampus is highest in slow-theta, temporal/frontal cortex in 4–9 Hz theta range.

Figure 4.

Comparison of PAC during successful and unsuccessful item encoding. (A) Histograms showing number of electrodes that exhibit a significant difference in magnitude of PAC (for gamma band coupling) for the slow-theta and 4–9 Hz theta bands. Percentage refers to fraction of electrodes from within each of 3 brain regions. Red segment at bottom indicates PAC− electrodes (greater PAC during unsuccessful encoding) and blue segment indicates PAC+. For hippocampus, asterisk indicates that counts for slow-theta band were significantly greater than for 4–9 Hz band. Red lines across the bars indicate the number of electrodes of the type I error rate. (B) Histogram compiling the preferred phase for PAC for the electrodes included in the histograms above (PAC+ and –). Red line indicates the mean phase value for the entire distribution. Highlighted box on left indicates group for which a significant difference in the distribution of phase values exists between PAC+ and PAC− electrodes (hippocampal slow-theta band) with PAC+ electrodes exhibiting a phase preference clustered at the trough of the oscillation.

Figure 5.

Relationship between hippocampal SME and PAC effects. Scatterplot of t statistic comparing slow-theta band power during successful and unsuccessful item encoding versus z value for PAC during item encoding across all hippocampal electrodes in the dataset. Plot illustrates a highly significant positive correlation between slow-theta SME and PAC differences during encoding. This indicates that as slow-theta power increases at a given electrode, the slow-theta oscillation more efficiently entrains gamma oscillations during successful encoding.