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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Science. Author manuscript; available in PMC Jan 16, 2009.
Published in final edited form as:
PMCID: PMC2628289
NIHMSID: NIHMS14964

High Gamma Power Is Phase-Locked to Theta Oscillations in Human Neocortex

Abstract

We observed robust coupling between the high- and low-frequency bands of ongoing electrical activity in the human brain. In particular, the phase of the low-frequency theta (4 to 8 hertz) rhythm modulates power in the high gamma (80 to 150 hertz) band of the electrocorticogram, with stronger modulation occurring at higher theta amplitudes. Furthermore, different behavioral tasks evoke distinct patterns of theta/high gamma coupling across the cortex. The results indicate that transient coupling between low- and high-frequency brain rhythms coordinates activity in distributed cortical areas, providing a mechanism for effective communication during cognitive processing in humans.

Neuronal oscillations facilitate synaptic plasticity (1), influence reaction time (2), correlate with attention (3) and perceptual binding (4), and are proposed to play a role in transient, long-range coordination of distinct brain regions (5). Direct cortical recordings reveal that ongoing rhythms encompass a wide range of spatial and temporal scales— ultraslow rhythms less than 0.05 Hz coexist with fast transient oscillations 500 Hz or greater (1), with spatial coherence between these oscillations extending from several centimeters for the corticospinal tract (6) to the micrometer scale for subthreshold membrane oscillations in a single neuron (7). Exactly how these transient oscillations influence each other and coordinate processing at both the single-neuron and population levels remains unknown.

Evidence for cross-frequency coupling, where one frequency band modulates the activity of a different frequency band, is more abundant in animal than human data. For example, the theta rhythm can modulate the firing rate and spike timing of a single neuron (811) as well as the gamma power of the intracortical local field potential (8, 12, 13). Task-related changes in theta power have been observed in humans (1416), and cross-frequency coupling at frequencies up to 40 Hz has been detected at the scalp (17, 18). However, given the difficulty in localizing electrical sources from scalp recordings alone (19), subdural electrodes that record directly from the human cortex are needed to address this question. Furthermore, subdural electrodes are ideal for studying activity in the recently described human high gamma band (HG) at 80 to 150 Hz. HG activity is modulated by sensory, motor, and cognitive events (20), is functionally distinct from low gamma (30 to 80 Hz) with different physiological origins (21), and is correlated with the functional magnetic resonance imaging blood oxygen level–dependent (fMRI BOLD) signal (2224). There have been no reports of coupling between any low-frequency rhythm and HG in signals recorded either at the scalp or directly from human sensory, motor, or association cortex. We therefore focus exclusively on theta/HG coupling in this report.

We analyzed multichannel subdural electrocorticogram (ECoG) data from five patients undergoing neurosurgical treatment for epilepsy. Typically, the events of interest in behavioral paradigms are the stimulus onsets and motor responses that evoke frequency-specific changes in the electrical activity of the brain. In contrast, the events of interest in cross-frequency coupling are features of the ongoing oscillatory activity itself. That is, cross-frequency coupling refers to statistical dependence between distinct frequency bands of the ongoing ECoG rather than dependence between the ECoG and external stimulus events. The dependence between two frequencies f1 and f2 can assume many forms, including coupling between the amplitude envelopes A1(t) and A2(t), the phase time series [var phi]1(t) and [var phi]2(t), or an amplitude-phase coupling between A1(t) and [var phi]2(t). We focus here on the last type of coupling and use an index of cross-frequency coupling that directly combines the amplitude envelope time series A1(t + τ) of a high-frequency band with the phase time series [var phi]2(t) of alow-frequency band into one composite, complex-valued signal z(t, τ). The (normalized) temporal mean of this composite signal provides a sensitive measure of the coupling strength and preferred phase between the two frequencies (25).

Animal evidence for theta phase modulation of single-unit firing and the strong connection of theta to learning, attention, and memory (26, 27) suggested to us that high-frequency oscillations in human neocortex may be modulated by the theta rhythm. Accordingly, we analyzed the ECoG across a range of behavioral tasks (25). Figure 1B shows a time-frequency plot for data recorded from an electrode over the left middle frontal gyrus during an auditory language–related target detection task (Fig. 1A, arrow). Theta trough–locked averaging of the normalized time-frequency plane shows significant coupling (P < 0.001, corrected) between theta phase and high-frequency power, with an increase or decrease in power relative to baseline occurring at the theta trough or peak. Theta coupling was broadband from ~20 to 200 Hz, with the strongest modulation occurring in the HG band. Fig. 1D and fig. S4, using the modulation index discussed above, also show that coupling is strongest between theta phase and HG amplitude.

Fig. 1.
High gamma (80 to 150 Hz) power is modulated by theta (4 to 8Hz) phase. (A) Structural MRI showing position of 64-channel ECoG grid over frontal and temporal lobes in subject 1. (B) Example of phase-locked modulation of power in the ECoG signal from an ...

Across all tasks and subjects, 252 out of 299 tested electrodes (84.3%) showed significant theta/gamma coupling (P < 0.001 for each electrode, corrected). Excluding the 60 electrodes over resected tissue (which includes both epileptic and healthy tissue) increases this percentage to 88.7%, whereas only 66.7% of electrodes over resected tissue showed significant coupling. The largest HG amplitudes tended to occur at the trough of the theta waveform in electrodes with strong coupling (Figs. 1C and and2A).2A). The coupling strength between the HG analytic amplitude time series AHG(t + τ) and theta analytic phase [var phi]TH(t) should decrease to chance levels as the magnitude of the time lag t increases. Figure 3A, displaying all ECoG electrodes for one subject, shows that this is indeed the case (see fig. S8 for all subjects).

Fig. 2.
Theta/HG coupling strength is a function of theta amplitude. (A) Theta/HG coupling strength and preferred theta phase. (Bottom) One theta cycle (schematic), from theta peak (0 radians) to trough (π radians) to peak (π radians). (Top) Modulation ...
Fig. 3.
Task-specific changes in the spatial pattern of theta/HG coupling strength. (A) Theta/HG coupling strength falls to chance at large time lags. Modulation index (25)asa function of lag for all electrodes over all tasks from subject 5. Electrodes are sorted ...

The strength of theta/HG coupling depends on theta power as well as theta phase. We observed stronger coupling in electrodes with greater mean theta amplitude (Fig. 2B). That is, HG amplitudes have a stronger theta phase preference at greater theta power, indicating that theta/HG coupling strength can be modulated by adjusting theta power in a local cortical region. This contrasts with the weak negative correlation observed between theta/HG coupling strength and mean HG amplitude (Fig. 2C and fig. S6). Thus, mean HG power and the strength of theta/HG coupling appear to reflect independent dimensions of cortical activity.

Task-dependent modulation of theta power has been shown in humans (26), prompting the hypothesis that theta/HG coupling may be task-dependent. Two examples of task-specific changes in the spatial pattern of theta/HG coupling strength over all electrodes in one subject are shown in Fig. 3, B and C. Figure 3D shows that behavioral tasks evoke distinct and reproducible patterns of coupling in this subject, with similar tasks evoking similar coupling patterns whereas different tasks evoked alternate patterns. Spatial patterns associated with two runs of similar tasks were positively correlated, whereas runs of different tasks exhibited a null or negative correlation. This trend held across all tasks and subjects, as shown by Fig. 3E. These results are consistent with the hypothesis that transient cross-frequency coupling modulates network engagement, enabling flexible control of cognitive processing.

Oscillations are rhythmic fluctuations in neuronal excitability that modulate both output spike timing and sensitivity to synaptic input (5). Therefore, effective communication between neuronal populations requires precise matching of the relative phase of distinct rhythms to axonal conduction delays. An oscillatory hierarchy operating across multiple spatial and temporal scales could regulate this proposed long-range communication (13). Basal forebrain cortical-projecting GABAergic (γ-aminobutyric acid–releasing) neurons are well positioned to control theta/HG coupling; these neurons preferentially synapse onto intracortical GABAergic neurons throughout the cortex, with disinhibitory spike bursts causing a brief increase in gamma power at the theta trough (28). Our observations that (i) HG power is modulated by theta phase, (ii) an increase in theta power strengthens theta/HG coupling, and (iii) the topography of theta/HG coupling is task-dependent support the hypothesis that cross-frequency coupling between distinct brain rhythms facilitates the transient coordination of cortical areas required for adaptive behavior in humans.

Supplementary Material

Supplementary

References and Notes

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29. This work was supported by the Rauch family, National Institute of Neurological Disorders and Stroke grant NS21135, NSF Fellowship 2004016118, and National Institute on Deafness and Other Communication Disorders grant F31DC006762. The authors thank P. Garcia and D. Filippi of the Department of Neurology, University of California San Francisco, for their help on electrical stimulation mapping and localizing epileptic tissue.
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