Anterior-Posterior Hippocampal Dynamics Support Working Memory Processing

Abstract

The hippocampus is a locus of working memory (WM) with anterior and posterior subregions that differ in their transcriptional and external connectivity patterns. However, the involvement and functional connections between these subregions in WM processing are poorly understood. To address these issues, we recorded intracranial EEG from the anterior and the posterior hippocampi in humans (seven females and seven males) who maintained a set of letters in their WM. We found that WM maintenance was accompanied by elevated low-frequency activity in both the anterior and posterior hippocampus and by increased theta/alpha band (3-12 Hz) phase synchronization between anterior and posterior subregions. Cross-frequency and Granger prediction analyses consistently showed that the correct WM trials were associated with theta/alpha band-coordinated unidirectional influence from the posterior to the anterior hippocampus. In contrast, WM errors were associated with bidirectional interactions between the anterior and posterior hippocampus. These findings imply that theta/alpha band synchrony within the hippocampus may support successful WM via a posterior to anterior influence. A combination of intracranial recording and a fine-grained atlas may be of value in understanding the neural mechanisms of WM processing.SIGNIFICANCE STATEMENT Working memory (WM) is crucial to everyday functioning. The hippocampus has been proposed to be a subcortical node involved in WM processes. Previous studies have suggested that the anterior and posterior hippocampi differ in their external connectivity patterns and gene expression. However, it remains unknown whether and how human hippocampal subregions are recruited and coordinated during WM tasks. Here, by recording intracranial electroencephalography simultaneously from both hippocampal subregions, we found enhanced power in both areas and increased phase synchronization between them. Furthermore, correct WM trials were associated with a unidirectional influence from the posterior to the anterior hippocampus, whereas error trials were correlated with bidirectional interactions. These findings indicate a long-axis specialization in the human hippocampus during WM processing.

Keywords: hippocampus; intracranial EEG; longitudinal axis; working memory.

Figure 1.

Working memory task, recording sites in the hippocampus, and time–frequency power. A, An example trial of the task. Each trial consisted of a set of consonants (encoding, 2 s), followed by a delay (maintenance, 3 s). After the delay, a probe letter was shown, and the subjects indicated whether the probe was or was not shown during the encoding period (retrieval, 2 s). B, Electrode location across subjects in Montreal Neurologic Institute (MNI152) space. Recording subregions are indicated by different colors (magenta, aHipp; cyan, pHipp). C, An example MRI and template for a single subject. D, Average task-induced power, grouped in the anterior hippocampus (left column) and posterior hippocampus (right column), across all subjects during the maintenance phase for the correct trials. Warmer colors denote task-increased power above the baseline, and colder colors denote task-decreased power. Both the aHipp and the pHipp showed sustained task-increased power in the low-frequency range (2–20 Hz; z > 1.96, p < 0.05) during the maintenance phase. E, Spectral z-scored power within the anterior (magenta) and posterior hippocampus (cyan) across all subjects (±SEM shown as shading around the mean trace) for the correct trials. During maintenance, no significant difference in the spectral power (p > 0.05, cluster-based permutation test) was found between the two subregions across the frequency band.

Figure 2.

Frequency-specific aHipp–pHipp phase synchrony during maintenance. A, Phase synchrony (PLV) between the anterior hippocampus and the posterior hippocampus was identified across all subjects, with greater theta/alpha synchrony during the maintenance for the correct trials. The PLVs ranged from 0 to 1, with warmer colors indicating greater PLVs. The PLV maps show the PLVs that survived the threshold at p < 0.05 (cluster-based permutation test). B, Spectral PLVs within 1–30 Hz between the aHipp and the pHipp across subjects for the correct trials (±SEM shown as shaded area around the mean trace) with peaks in the theta/alpha band (3–12 Hz, shading in light orange). The shaded area indicates the theta/alpha range used for the subsequent analyses. C, Extracted theta/alpha PLVs of the aHipp–pHipp across all subjects for the baseline and maintenance in the correct trials. The theta/alpha PLVs were elevated by the maintenance relative to the baseline (paired t test, t₍₈₃₎ = 3.97, p = 0.0002). D, The GC index for the correct trials was extracted within the theta/alpha band across subjects for two directions (magenta: aHipp to pHipp; cyan: pHipp to aHipp). Stronger GC was found for pHipp to aHipp (cyan) than for aHipp to pHipp (magenta; mixed-effect model, *p < 0.05).

Figure 3.

Cross-frequency coupling between the aHipp and the pHipp. A, Average cross-frequency phase–amplitude coupling (z score) between the anterior hippocampus and posterior hippocampus across all subjects for correct trials. To assess the task-induced effects, the z-scored PAC during the maintenance was compared with the baseline values by the cluster-based permutation test. A one-tailed test was applied to find the task-increased coupling relative to the baseline (p < 0.05). For the theta–alpha phase (3–12 Hz)/gamma amplitude (30–100 Hz) coupling shown in the orange boxes, interregional modulations for both directions were significantly higher during maintenance relative to those in the baseline period (all p values < 0.05). B, The theta/alpha–gamma (orange box) PACs were calculated across subjects for two directions (magenta, aHipp–pHipp means aHipp phase modulating pHipp amplitudes; cyan, pHipp–aHipp means the reverse direction) for the correct trials. The modulation strength from the pHipp to the aHipp was greater than that from the aHipp to the pHipp (mixed-effect model, **p < 0.01). C, Average z-scored intrahippocampal PAC for the slow-theta (3–5 Hz)–gamma, fast-theta (5–9 Hz)–gamma, and alpha (9–12 Hz)–gamma PACs between the aHipp and the pHipp in both phase–amplitude combinations (low-frequency phase from the aHipp and alpha amplitude from the pHipp, and vice versa). For each frequency band, the coupling strength between the pHipp phase and the aHipp amplitude (pHipp–aHipp, cyan) was consistently greater than that between the aHipp phase and the pHipp amplitude (aHipp–pHipp, magenta). D, Computation of theta/alpha–gamma interactions. Phase–amplitude distributions were constructed for both directions (top: magenta, gamma amplitudes of the pHipp distributed across the theta/alpha phase bins of the aHipp, abbreviated as aHipp–pHipp; cyan, gamma amplitudes of the aHipp distributed across the theta/alpha phase bins of the pHipp, abbreviated as pHipp–aHipp). The difference distributions were obtained by subtracting the aHipp–pHipp from the pHipp–aHipp (bottom, orange). The gamma activity from both the aHipp (magenta) and the pHipp (cyan) was modulated by the theta/alpha oscillations around the trough (Rayleigh test, average pHipp gamma amplitude occurred at 57.3°, p_pHipp = 4.31 × 10⁻⁸; average aHipp gamma amplitude occurred at 57.2°, p_aHipp = 4.31 × 10⁻⁸). The difference distributions were not uniform (Rayleigh test, p = 4.31 × 10⁻⁸).

Figure 4.

Directionality of the aHipp–pHipp for the incorrect trials. A, The GC index for the incorrect trials was extracted within the theta/alpha band across subjects for two directions (magenta, aHipp to pHipp; cyan, pHipp to aHipp). No difference in GC was found between the aHipp and the pHipp for either direction (mixed-effect model, p > 0.05). B, Schematics of the maintenance of WM processing within the hippocampus for the correct trials (left) and the incorrect trials (right). Directional information flow driven by the pHipp to the aHipp within the theta/alpha band subserved the correct performance in the WM trial, but this bias with respect to the directionality of information transfer was absent in incorrect WM trials.

Figure 5.

Power and phase synchrony for the incorrect trials. A, Average task-induced power across all subjects during maintenance for the incorrect trials, grouped in the anterior (left column) and posterior hippocampus (right column). Warmer colors denote task-increased power from the baseline and colder colors denote task-decreased power. Task-induced effects on both the aHipp and the pHipp were not sustained during maintenance in the low-frequency range (2–20 Hz; z < 1.96) for the incorrect trials. B, Spectral z-scored power within the anterior (magenta) and posterior hippocampus (cyan) across all subjects (±SEM shown as shading around the mean trace) for the incorrect trials. The spectral power was not significant (z < 1.96) during maintenance, and no significant difference (p > 0.05, clustered-based permutation test) was found between the two subregions across the frequency band. C, Significant PLVs above the thresholds (p < 0.05. permutation test) across the time–frequency domain were present between the aHipp and the pHipp for the incorrect trials. Only a few scattered points survived testing for incorrect trials. Therefore, the PLV of incorrect trials was not further analyzed.

Figure 6.

PLV and GC analyses with a bipolar reference. A, Average phase synchronization (z-scored PLV) across electrode pairs for the correct trials, with a bipolar reference. Elevated PLV in the low-frequency band was sustained throughout the entire maintenance period. B, Granger causality between hippocampal subregions from both directions by using a bipolar reference for the correct trials. #p < 0.1. GC values from the pHipp to aHipp are higher than those in the opposite direction with a trend toward statistical significance (mixed-effect model, p = 0.092).