Theta Oscillations in the Human Medial Temporal Lobe during Real-World Ambulatory Movement

Abstract

The theta rhythm-a slow (6-12 Hz) oscillatory component of the local field potential-plays a critical role in spatial navigation and memory by coordinating the activity of neuronal ensembles within the medial temporal lobe (MTL). Although theta has been extensively studied in freely moving rodents, its presence in humans has been elusive and primarily investigated in stationary subjects. Here we used a unique clinical opportunity to examine theta within the human MTL during untethered, real-world ambulatory movement. We recorded intracranial electroencephalographic activity from participants chronically implanted with the wireless NeuroPace responsive neurostimulator (RNS) and tracked their motion with sub-millimeter precision. Our data revealed that movement-related theta oscillations indeed exist in humans, such that theta power is significantly higher during movement than immobility. Unlike in rodents, however, theta occurs in short bouts, with average durations of ∼400 ms, which are more prevalent during fast versus slow movements. In a rare opportunity to study a congenitally blind participant, we found that both the prevalence and duration of theta bouts were increased relative to the sighted participants. These results provide critical support for conserved neurobiological characteristics of theta oscillations during ambulatory spatial navigation, while highlighting some fundamental differences across species in these oscillations between humans and rodents.

Keywords: MTL; NeuroPace responsive neurostimulator; human; medial temporal lobe; navigation; theta oscillations; wireless intracranial recordings.

Figure 1. Simultaneous motion tracking and iEEG recording within the human MTL

(A) Example post-operative CT of a participant with an implanted electrode in the right hippocampus (top left) along with a coronal view of a high-resolution MRI overlaid with co-registered electrodes (shown in yellow). (B) Sample trajectory of a participant during one complete trial consisting of linear and circular movements. (C) Schematic of the setup of cameras used for motion capture (see STAR Methods). Inset: Real time motion tracking of an example participant. (D) Movement speed distribution of all sighted participants (green; median, [25^th, 75^th] = 0.87, [0.20, 1.14] m/s, N_{trials×channels} = 84) and congenitally blind participant (black; median, [25^th, 75^th] = 0.44, [0.05, 0.68] m/s, N_{trials×channels} = 28); dashed vertical lines indicate median value; shaded areas correspond to kernel smoothing function estimates of the distributions). See also Tables S1, S2, and Movie S1.

Figure 2. Example theta oscillations in the human MTL

(A) Example one-second-long raw iEEG traces (gray) from the MTL of all study participants overlaid with filtered (3–12Hz) theta oscillations (hippocampal and entorhinal theta shown in red and blue respectively). Participant P3 is congenitally blind. Note that on average, the duration of theta bouts are shorter than 1s as demonstrated in this figure (for a detailed characterization, see Figure 4). (B) Left) Sample electrode locations from a participant (P2) overlaid onto coronal pre-operative high-resolution MRI. Right) Automated MTL subregion segmentation (note that different colors correspond to different areas) demonstrating electrode locations in an example participant. White areas correspond to white matter. See also Figures S1, S6, Table S3, and Movies S2, S3.

Figure 3. Theta power during movement versus periods of immobility

(A) Example (normalized) power spectra from a sighted participant (P1, top, green) and the congenitally blind participant (P3, bottom, black) displaying more theta power during movement (solid lines) compared to immobility (dashed lines). The power spectrum for each trial was normalized by the average power in that trial, during movement and immobility, over the frequency range 3–12Hz. Values below 4 Hz (lower range of the analog bandpass filter) are marked with shaded gray areas. Channel names are labeled clinically and for a detailed description, see Table S3. The recordings were bipolar using adjacent electrodes 1–2 and 3–4 (e.g. REC1-REC2 is one iEEG channel). The two adjacent electrodes in iEEG channel REC1-REC2 in participant P1 were located in the right entorhinal cortex (REC1) and right perirhinal cortex (REC2). The two adjacent electrodes in iEEG channel LEC1-LEC2 in participant P3 were located in the left entorhinal cortex (LEC1) and left perirhinal cortex (LEC2). (B) Theta power index was significantly positive for all participants as shown above, thus indicating higher theta power during movement (sighted participants (green); P1: 0.50, [0.43, 0.57], p=3.79×10⁻¹⁶; P2: 0.29, [0.27, 0.36], p=8.86×10⁻⁵; P5: 0.39, [0.24, 0.43], p=2.36×10⁻⁷; congenitally blind participant (black); P3: 0.45, [0.35, 0.50], p=3.79×10⁻⁶_; Wilcoxon signed rank test was used because not all of the distributions passed the Lilliefors test of normality). Shaded area corresponds to kernel smoothing function estimate of the distribution and the dashed line indicates the median value. See also Figure S2, Table S3.

Figure 4. Significant increase in the prevalence of high-frequency theta oscillations during fast compared to slow movement

(A) Colormap shows percentage of time with significant oscillations (p-episode) in the frequency range indicated on the x axis averaged across trials for each clinically labeled channel in the left and right entorhinal cortex (LEC, REC) and left and right hippocampus (LHIP and RHIP) from all participants (electrode 1: most distal, electrode 4: most proximal; The electrodes were implanted orthogonal to the surface of the brain, thus distal and proximal correspond to deeper and shallower contacts respectively). Channel names are labeled clinically; for a detailed description of the localizations, see Table S3. Data are normalized by the maximum value for each channel, within each condition, for visibility purposes (range: 0–1). Brighter colors indicate larger values as demonstrated by the colorbars. Throughout this figure, red shades and blue shades correspond to fast and slow movements respectively. Also, note that for each participant, channels are sorted based on the frequency with maximum prevalence during fast movements, i.e. the frequency with maximum p-episodes in each channel increases from top to bottom rows. Left: Shown are normalized p-episodes during fast movement. Lighter shades indicate higher values here and throughout figures (N_trials for participants P1, P2, P5 and P3 (congenitally blind) were 7, 5, 9 and 7 respectively). Right: Same as (left) but during movement at slow speeds. (B) Percentage of time with significant oscillations (across all trials and channels; shown are mean ± s.e.m) during fast movements (red) versus slow movements (blue) in 3 sighted participants (top, N_{trials×channels}=84) and 1 congenitally blind participant (bottom, N_{trials×channels}=28). Black horizontal lines indicate regions with significant difference in p-episodes between fast and slow movement conditions (p < 0.05, clustered-based permutation test). Values below 4 Hz (lower range of the analog bandpass filter) are marked with shaded gray areas. See also Figures S3, S4, S5, and Table S3.

Figure 5. Theta oscillations are more prevalent during head-scanning behavior

(A) Example raw iEEG trace (gray) from a participant (P5) overlaid with filtered (3–12Hz) theta oscillations (blue) while he walked down the same path with and without head-scanning left and right. Green trace demonstrates the angular velocity of the head. (B) The participant was able to perform the task and periods with head-scanning behavior (red) manifested higher head angular speed (dashed line denotes the median value). (C) Head-scanning behavior resulted in higher presence of theta oscillations (red curve: p-episode = 21.73±4.47% at peak frequency of 7.75Hz) compared to periods when the participant walked looking at a fixed target (blue curve; p-episode = 10.09±3.85% at 7.75Hz). Shown are the mean ± s.e.m. values. Values below 4 Hz (lower range of the analog bandpass filter) are marked with shaded gray areas.

Figure 6. Duration of theta bouts is similar during fast and slow movements

(A) Colormaps indicate percentage of time with significant oscillations (p-episodes) in each frequency (averaged across trials, channels and participants) assuming varying number of minimum cycles for detection (y-axis). Red and blue color schemes correspond to fast and slow movements respectively, here and throughout the figure. Number at the top right corner indicates range. (B) Duration of significant oscillations at each frequency is shown as mean ± s.e.m across all trials and channels. There was no significant difference between the duration of the bouts between fast (red) and slow (blue) movements. However, note that in the congenitally blind participant (right), the duration of theta bouts (0.57s at peak frequency of 7.75Hz) were longer than those in the sighted participants (left, 0.44s at peak frequency of 7.25Hz). Values below 4 Hz (lower range of the analog bandpass filter) are marked with shaded gray areas.