Cross-frequency coupling supports multi-item working memory in the human hippocampus

Abstract

Recent findings indicate that the hippocampus supports not only long-term memory encoding but also plays a role in working memory (WM) maintenance of multiple items; however, the neural mechanism underlying multi-item maintenance is still unclear. Theoretical work suggests that multiple items are being maintained by neural assemblies synchronized in the gamma frequency range (25-100 Hz) that are locked to consecutive phase ranges of oscillatory activity in the theta frequency range (4-8 Hz). Indeed, cross-frequency coupling of the amplitude of high-frequency activity to the phase of slower oscillations has been described both in animals and in humans, but has never been linked to a theoretical model of a cognitive process. Here we used intracranial EEG recordings in human epilepsy patients to test pivotal predictions from theoretical work. First, we show that simultaneous maintenance of multiple items in WM is accompanied by cross-frequency coupling of oscillatory activity in the hippocampus, which is recruited during multi-item WM. Second, maintenance of an increasing number of items is associated with modulation of beta/gamma amplitude with theta band activity of lower frequency, consistent with the idea that longer cycles are required for an increased number of representations by gamma cycles. This effect cannot be explained by a difference in theta or beta/gamma power. Third, we describe how the precision of cross-frequency coupling predicts individual WM performance. These data support the idea that working memory in humans depends on a neural code using phase information.

Fig. 1.

Theta-beta/gamma modulation in the human hippocampus during working memory maintenance. Cross-frequency coupling during WM maintenance (A) was larger than during the baseline period (B) in the human hippocampus (all figures depict grand averages across subjects). Modulation peaked at 7 Hz for the lower-frequency (modulating) theta oscillations and at 28 Hz for the high (modulated) beta/gamma oscillations. (C and D) Cross-frequency coupling in scrambled surrogate data and in surrogate data obtained by randomly assigning trials for gamma power and trials for theta phase. (E) Remaining cross-frequency coupling in these surrogates can be explained by fluctuations of gamma power time series at theta frequency. FFT, fast Fourier transform. (F) Depiction of modulation strength at the phase for which modulation was maximal in each trial indicates that modulation of beta/gamma amplitude reaches its maximum at a theta phase around 0°. (G) Cross-frequency coupling occurred during consecutive theta cycles in the maintenance period. Power values in a range of 1–50 Hz are triggered to the peak of consecutive theta cycles. Data were first averaged across all trials in each patient, and then averaged across all patients. The vertical axis represents frequency (between 1 and 50 Hz) in each cycle. The horizontal axis is plotted in units of time because we extracted power values from −75 ms to +75 ms triggered to the peak of the consecutive theta cycles (on average, −75 ms and +75 ms correspond to the troughs and 0 ms to the peak of theta band activity).

Fig. 2.

Time-domain data and grand average of power data. (A) Unfiltered raw data in a single trial indicate both slow and fast oscillatory activity. Vertical gray lines indicate visually detected maxima of slow activity. (B) Modulation of beta/gamma by theta phase in the same trial filtered at 7 Hz and 28 Hz. (C) Grand average of the distribution of beta/gamma power at 28 Hz across all theta phases at 7 Hz. Error bars depict SEM. (D) Grand average of the power spectrum shows a peak in the theta frequency range between 7 and 8 Hz.

Fig. 3.

Modulation frequency depends on working memory load. (A) Cross-frequency coupling in the different load conditions. (B) The frequency of modulating theta oscillations shifts toward lower frequencies with increasing memory load (colored circles indicate values for individual subjects). (C) In contrast, there was no significant change of the modulated frequency due to high interindividual variability. (D) Constant ratio of modulating and modulated frequency. Similar power spectra (E) and constant power at 7 Hz and 28 Hz (F) in the different load conditions. Error bars indicate SEM.

Fig. 4.

Properties of cross-frequency coupling for multiple items and relationship with behavior. Effect of load on modulation width (A), circular variance of the distributions of modulation phase across trials (B), and modulation strength (C). (Circular variance and modulation strength are dimensionless quantities.) Modulation width was negatively correlated with the number of correct trials over subjects in the load 1 condition, indicating that modulation in a narrower phase range predicts faster reactions times during working memory (D). Error bars indicate SEM.