Human retrosplenial cortex displays transient theta phase locking with medial temporal cortex prior to activation during autobiographical memory retrieval

Abstract

The involvement of retrosplenial cortex (RSC) in human autobiographical memory retrieval has been confirmed by functional brain imaging studies, and is supported by anatomical evidence of strong connectivity between the RSC and memory structures within the medial temporal lobe (MTL). However, electrophysiological investigations of the RSC and its interaction with the MTL have mostly remained limited to the rodent brain. Recently, we reported a selective increase of high-frequency broadband (HFB; 70-180 Hz) power within the human RSC during autobiographical retrieval, and a predominance of 3-5 Hz theta band oscillations within the RSC during the resting state. In the current study, we aimed to explore the temporal dynamics of theta band interaction between human RSC and MTL during autobiographical retrieval. Toward this aim, we obtained simultaneous recordings from the RSC and MTL in human subjects undergoing invasive electrophysiological monitoring, and quantified the strength of RSC-MTL theta band phase locking. We observed significant phase locking in the 3-4 Hz theta range between the RSC and the MTL during autobiographical retrieval. This theta band phase coupling was transient and peaked at a consistent latency before the peak of RSC HFB power across subjects. Control analyses confirmed that theta phase coupling between the RSC and MTL was not seen for other conditions studied, other sites of recording, or other frequency ranges of interest (1-20 Hz). Our findings provide the first evidence of theta band interaction between the human RSC and MTL during conditions of autobiographical retrieval.

Figures

Figure 1.

Experimental task and electrode localization. a, All subjects performed a simple behavioral task requiring true/false (button press “1”/“2”) judgments of either autobiographical statements (self-episodic) or arithmetic equations (math) as previously described (Foster et al., 2012). These conditions had a variable RT duration and were randomly interleaved by a fixed 5 s rest period (rest). The interstimulus interval (ISI) was 200 ms; however, no ISI followed the occurrence of rest trials. b, Intracranial electrodes were localized in each subject by aligning post implant CT images with preoperative higher resolution MRI images, and then projecting electrode coordinates to the segmented cortical surface (Hermes et al., 2010). Adapted from Foster et al., 2012 with permission. c, Electrodes were anatomically classified in each subject using common sulcal and gyral landmarks on the ventromedial surface. pos, parieto-occipital sulcus; cos, collateral sulcus; RSC, retrosplenial cortex; PHG, parahippocampal gyrus; ERC, entorhinal cortex (Parvizi et al., 2006; Weiner and Grill-Spector, 2013).

Figure 2.

Data analysis. a, Using subdural electrodes (e.g., linear strip arrays) raw ECoG signals (voltage) are recorded from each electrode (i–ii; electrodes A and B), initially referenced to a clinically chosen site elsewhere. These raw signals are then pairwise re-referenced using a sequential next-neighbor bipolar subtraction, which is simply the pointwise voltage difference between two adjacent electrodes (iii; e.g., electrode A–electrode B, B–C, C–D, D–E). Each differentiated channel pair of interest (e.g., A–B, Region 1 = R1) is filtered (convolved with a wavelet) for a specific frequency (e.g., 4 Hz) to obtain a complex valued time series containing instantaneous amplitude (iv; an) and phase (v; φn) information (note: phase φn is shown here as cos φn). b, To quantify phase locking between two regions of interest (e.g., R1 and R2), the time-varying phase values (φR1n and φR2n) are first determined as in a. For a given condition of interest the trial averaged PLV can be estimated at each time point following stimulus presentation. Across trials, the angular difference between the two phase series from R1 and R2 is calculated for the same time point with respect to stimulus onset. For a given time point tTN + τ (where N is trial number and τ is time from stimulus onset), the phase difference is calculated (e.g., φR1T1 + τ − φR2T1 + τ for trial 1). c, Collecting the phase angle difference of each trial provides, for the time point of interest, a circular distribution of unit vectors in the complex plane, the average of which is the PLV (red lines indicate example trials 1–3 shown in b; synthetic data). Therefore, the PLV is the circular mean (absolute vector length) of all the trials for that time point. d, By repeating this calculation for each time point with respect to stimulus onset the time resolved PLV for a particular condition is constructed.

Figure 3.

Electrode locations and theta phase-locked regions. a–d, Medial view of electrode locations for each of the four subjects (S; M = male, F = female) showing coverage over the RSC (orange) and MTL (turquoise). As bipolar referencing is used, some electrodes are included (colored) because they were part of an electrode pair with one electrode being within the region of interest. Theta band phase locking was tested for all possible RSC–MTL combinations in each subject for each condition (self-episodic, math, and rest). Significant theta band phase locking was only observed for the self-episodic condition (i.e., contained PLV time points with *p < 0.05 when compared with surrogate data; see Materials and Methods). Only one set of RSC–MTL sites was identified as significant in each subject for the self-episodic condition. The significantly coupled RSC–MTL pairs for the self-episodic condition are highlighted for each subject. Bar plots show the related change in raw theta band PLV across conditions for the highlighted electrode pairs. These change values reflect the mean PLV value averaged over a poststimulus window of 0–500 ms, after being normalized to the prestimulus period. Means and SE (error bars) were estimated using resampling statistics (see Materials and Methods). Note that while changes in PLV for the math and rest condition may differ and be above zero, these values were not significantly different from surrogate data (p > 0.05).

Figure 4.

HFB power change in RSC and MTL. Bars display the mean change (with SE) in HFB power across conditions (self-episodic, math, and rest) for the RSC (a) and MTL (b) sites that showed significant theta phase locking during the self-episodic condition (poststimulus window = 400–1000 ms; all subjects). Only RSC sites displayed significant differences in HFB power across conditions (*p < 0.05).

Figure 5.

RSC–MTL theta phase locking precedes RSC HFB power. a–d, Temporal dynamics of the raw theta band PLV for RSC–MTL coupling (red; right y-axis) and RSC HFB power (black; left y-axis) relative to stimulus (stim.) onset for the self-episodic condition across subjects (S1–S4). Theta band PLV frequencies are S1 = 4 Hz, S2 = 4 Hz, S3 = 4 Hz, and S4 = 3 Hz (see Results). Shading on both traces reflects SEM. Dashed red line (a–d) is the mean of maximal surrogate PLV values for each subject. Across subjects, theta band PLV between RSC–MTL transiently increases and peaks before the peak of RSC HFB activity.

Figure 6.

RSC–MTL phase locking is specific to the theta band range. a, Example time-frequency plots (shown for S2) of phase locking between RSC and MTL pairs for each condition (color map indicates –log(p) value based on comparison with surrogate data, e.g., –log(0.05) = 2.99). Phase locking was specific to the theta band range and centered around 3–4 Hz, only for the self-episodic condition. b, Distribution of mean (with SE) surrogate controlled PLV across all subjects (S1–S4) for each condition, estimated by averaging values from 0 to 500 ms after stimulus onset (note: p values are lower than observed maximal values because of temporal averaging). Mean PLV distributions show a main 3–4 Hz peak and also a minor secondary 8 Hz peak for the self-episodic condition, whereas math and rest conditions are comparatively flat.