Review
The functional role of cross-frequency coupling

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Recent studies suggest that cross-frequency coupling (CFC) might play a functional role in neuronal computation, communication and learning. In particular, the strength of phase-amplitude CFC differs across brain areas in a task-relevant manner, changes quickly in response to sensory, motor and cognitive events, and correlates with performance in learning tasks. Importantly, whereas high-frequency brain activity reflects local domains of cortical processing, low-frequency brain rhythms are dynamically entrained across distributed brain regions by both external sensory input and internal cognitive events. CFC might thus serve as a mechanism to transfer information from large-scale brain networks operating at behavioral timescales to the fast, local cortical processing required for effective computation and synaptic modification, thus integrating functional systems across multiple spatiotemporal scales.

Section snippets

Neuronal oscillations and brain function

What role, if any, do neuronal oscillations play in shaping computation and communication in large-scale brain networks? There is increasing interest in this question for several reasons. First, electrical brain activity is now commonly recorded at a variety of different scales, each of which exhibits oscillatory activity correlated with functional activation. Recordings from these different spatial scales include not only spikes from single neurons, but also measures of synchronized population

Evidence of CFC

This review focuses primarily on phase–amplitude CFC, but other types of coupling across frequencies exist. Two other varieties of coupling that have been studied are cross-frequency phase synchronization (phase–phase CFC), and cross-frequency amplitude envelope correlation (amplitude–amplitude CFC).

It has been suggested that phase synchronization plays a number of different roles in brain function. Cross-location, same-frequency phase coupling between different brain areas has been studied

Dynamic entrainment of low-frequency phase

It is possible that phase–amplitude CFC exists but is unrelated to functional activity, computation or communication. However, recent research has shown that low-frequency activity can be entrained by rhythmic external sensory and motor events 56, 57, 58, as well as internal cognitive processes related to learning and memory [59]. Therefore, low-frequency phase entrainment combined with the presence of phase–amplitude CFC implies that the modulation of high-frequency power by CFC will be

Cellular and network origins of phase–amplitude CFC

It is critical to distinguish between two different ways of thinking about CFC: (i) as an observed statistical dependence between filtered signals derived from electrical brain activity and (ii) as a transient but mechanistic coupling (mediated by spikes and synaptic activity) between the functionally distinct neuronal subpopulations that give rise to recorded electrical activity. CFC can have a functional role under option ii, but not under option i. Therefore, saying that theta–gamma

Dynamic and transient CFC

Low-frequency phase entrainment to behaviorally relevant events suggests a functional role for phase–amplitude CFC, but CFC could not serve as an effective control mechanism if CFC strength were constant over time and across different tasks. The findings of Tort and colleagues are illuminating because they showed dynamic modulation of CFC strength in rodent hippocampus and striatum during a simple T-maze task [37]. Interestingly, in addition to showing that CFC strength can quickly go from no

CFC and learning

The findings described above, which show that CFC can be entrained to behavioral events and dynamically and independently modulated in multiple task-relevant areas, support the claim that phase–amplitude CFC has a functional role but does not provide a clear and unambiguous link to performance. Such a link is provided by a recent study showing a strong correlation between CFC strength and performance in a learning task [39]. In this learning task the strength of hippocampal CFC increased over

Concluding remarks

In the past decade, several lines of research have converged on the notion that phase–amplitude CFC plays an important functional role in local computation and long-range communication in large-scale brain networks. The discovery that strong CFC exists in multiple brain areas, including the neocortex, hippocampus and basal ganglia, suggests that CFC reflects functional activation of these areas. The finding that the exact frequencies coupled together vary as a function of area and task implies

Glossary

Amplitude (envelope)
instantaneous magnitude of a complex-valued signal. Intuitively, a function that interpolates from peak to peak for an oscillatory waveform.
Frequency (band)
oscillations generated by active neuronal tissue often exhibit characteristic rhythms. Traditionally, neuronal oscillations have been divided into different bands, including slow oscillations (<1 Hz) and delta (1–4 Hz), theta (4-8 Hz), alpha (8–12 Hz), beta (12–30) and gamma (>30 Hz) bands, with further subdivisions becoming

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