Sleep-dependent theta oscillations in the human hippocampus and neocortex

Abstract

Hippocampal theta waves recorded during rapid eye movement (REM) sleep are thought to play a critical role in memory consolidation in lower mammals, but previous attempts to detect similar theta oscillations in the human hippocampus have been unsuccessful. Using subdural and depth recordings from epileptic patients, we now report the first evidence of state-dependent hippocampal theta waves (4-7 Hz) in humans. Unlike the continuous theta in rodents, however, these oscillations were consistently observed during REM sleep in short (approximately 1 sec) bursts and during transitions to wake in longer epochs. Theta waves were also observed in the basal temporal lobe and frontal cortex during transitions from sleep to wake and in quiet wakefulness but not in REM, and they were not coherent with hippocampal theta oscillations. The absence of functional coupling between neocortex and hippocampus during theta periods indicates that multiple theta generators exist in the human brain, and that they are dynamically regulated by brain state. Gamma oscillations were also present during REM theta bursts, but the fluctuations in gamma power were not associated with theta phase, pointing out another significant difference between rodent and human theta properties. Together, these findings suggest that the generation mechanisms of theta oscillations in humans might have evolved from tonic to phasic in hippocampus during REM sleep and extended from hippocampus to cortex, where they appear in certain wakefulness-related states.

Figure 1.

A, High-speed computed tomography view of the bilateral localization of multicontact depth electrodes in one of the participants. Aligned white dots correspond with the positions of the electrodes. B, Locations of recordings sites across all nine participants. These topographic maps show electrode locations on four views of a standard brain. Top left, Right lateral view. Top right, Left lateral view. Bottom left, Inferior view. Bottom right, Mid-axial-hippocampal view. Different shapes denote locations in different participants. Color-filled shapes indicate electrodes showed state-dependent θ oscillations. Note that some similar depth electrodes (bottom right, blue) showed θ oscillations during both REM and arousals from sleep.

Figure 2.

Human θ oscillations generated in the hippocampal formation during awakenings from natural sleep and during REM sleep in bursts. A, Examples of unfiltered EEG traces containing hippocampal θ oscillations associated with awakenings and REM bursts in one patient. Talairach coordinates (L-R, A-P, I-S) (in mm): (24.0, -26.9, -7.2). Identical findings were observed in the remaining two patients (Talairach coordinates: 24.0, -32.3, 1.1; and 24.0, -32.1, -0.8). The same electrodes exhibited maximal θ power during awakenings and REM θ. B, Spectra obtained from the EEG segments shown in A (thin lines) and from averaging all θ segments (thick lines) in the same hippocampal electrode for that patient. Mean frequencies are shown for averaged segments.

Figure 3.

Comparison of θ-burst activity in REM sleep and SWS. A, Representative pattern of θ power within the human hippocampus across 30 min of REM and SWS in a patient with hippocampal-depth electrodes as determined by the discrete-Fourier transform algorithms. The horizontal dashed line indicates the spectral power threshold used to quantify the number of θ bursts in each brain state. The threshold was computed using the averaged peak of θ power per minute during the entire period of each cerebral state. Talairach coordinates (L-R, A-P, I-S) (in mm): (24.0, -32.1, -0.8). B, Enlarged view of 1 min (indicated by the short, thick, black line under both plots in A) of θ power across time during REM and SWS, emphasizing the presence of short θ bursts selectively during REM sleep. C, Histogram of REM-θ burst durations computed for the same patient and recording site. Results similar to those shown in A-C were obtained in the other two patients with hippocampal recordings as well.

Figure 4.

Human θ oscillations in different regions of the neocortex during quiet wakefulness. A, Approximate location of the electrodes that showed the maximum amplitude of θ activity in five of eight patients with neocortical recordings (each symbol denotes a different patient). Talairach coordinates (L-R, A-P, I-S) (in mm): •, 14.8, 13.3, 41.2; ♦, -20.2, 47.7, 8.9; ▴, -29.0, 0.4, -27.4; ✚, -60.5, -26.9, -11.4; and ★, -44.1, -44.8, -15.7). B, Unfiltered EEG recordings from locations indicated in A. Note that each EEG trace belongs to a different patient and is highly representative of the pattern of electrophysiological activity observed during quiet wakefulness in each individual patient. For each patient, most of the electrodes placed within the same cortical region showed the same pattern of θ oscillations during quiet wakefulness. C, Spectral power density computed for a representative electrode in each neocortical region involved in θ generation during quiet wakefulness. Thick lines, Averaged spectra for all θ epochs; thin lines, spectra for single epochs shown in B. Peak frequencies are for averaged spectra.

Figure 5.

Evidence of different θ generator sources within the human hippocampal formation and neocortex. A, Averaged partial coherence results between pairs of electrodes for each wake-sleep state after removing common influences from other sources. Electrode pairs were located within the hippocampal formation (hipp-hipp; coordinates: 24.0, -26.9, -7.2; and 24.0, -36.2, 3.1), the basal surface of the temporal lobe (ctx-ctx; coordinates: -29.0, 0.4, -27.4; and -43.8, -38.3, -14.6), or had one electrode in each structure (hipp-ctx; coordinates: 24.0, -26.9, -7.2; and -29.0, 0.4, -27.4). B, Comparison of averaged θ power (4-7 Hz) within hippocampus and neocortex for each wake-sleep state. Data are from the same subject as in A. C, Same as A, but for a different patient. Corticocortical coupling in this patient was determined using a pair of electrodes located in the frontal lobe. Talairach coordinates (in mm): hipp-hipp, 24.0, -32.1, -0.8, and 24.0, -15.7, -12.1; ctx-ctx, 14.8, 13.3, 41.2, and 25.0, 21.9, 31.2; hipp-ctx, 24.0, -32.1, -0.8, and 14.8, 13.3, 41.2. D, Same as B, but for the patient shown in C. Results for both partial coherence and spectral analysis were essentially unchanged when other combinations of electrodes were used in each patient.

Figure 6.

Absence of phase relationship between θ cycle and γ amplitude in human hippocampus. Averaged peak of γ amplitude (bottom, thick line) showed an inconsistent relationship with the θ cycle (top) as revealed by the high variability observed in γ peak (±SD values represented by thin lines). θ cycle (top) was obtained after averaging all θ cycles contained in REM-θ bursts recorded in three patients with hippocampal implants.