Widespread ripples synchronize human cortical activity during sleep,waking, and memory recall

Declarative memory encoding, consolidation, and retrieval require the integration of elements encoded in widespread cortical locations. The mechanism whereby such “binding” of different components of mental events into unified representations occurs is unknown. The “binding-by-synchrony” theory proposes that distributed encoding areas are bound by synchronous oscillations enabling enhanced communication. However, evidence for such oscillations is sparse. Brief high-frequency oscillations (“ripples”) occur in the hippocampus and cortex and help organize memory recall and consolidation. Here, using intracranial recordings in humans, we report that these ∼70-ms-duration, 90-Hz ripples often couple (within ±500 ms), co-occur (≥ 25-ms overlap), and, crucially, phase-lock (have consistent phase lags) between widely distributed focal cortical locations during both sleep and waking, even between hemispheres. Cortical ripple co-occurrence is facilitated through activation across multiple sites, and phase locking increases with more cortical sites corippling. Ripples in all cortical areas co-occur with hippocampal ripples but do not phase-lock with them, further suggesting that cortico-cortical synchrony is mediated by cortico-cortical connections. Ripple phase lags vary across sleep nights, consistent with participation in different networks. During waking, we show that hippocampo-cortical and cortico-cortical coripples increase preceding successful delayed memory recall, when binding between the cue and response is essential. Ripples increase and phase-modulate unit firing, and coripples increase high-frequency correlations between areas, suggesting synchronized unit spiking facilitating information exchange. co-occurrence, phase synchrony, and high-frequency correlation are maintained with little decrement over very long distances (25 cm). Hippocampo-cortico-cortical coripples appear to possess the essential properties necessary to support binding by synchrony during memory retrieval and perhaps generally in cognition.

Ripples are brief high-frequency oscillations that have been well-studied in the rodent hippocampus during non-rapid eye movement sleep (NREM), when they mark the replay of events from the previous waking period, and are critical for memory consolidation in the cortex (1–4). Recently, ripples were found in rat association cortex but not primary sensory or motor cortices during sleep, with increased coupling to hippocampal ripples in sleep following learning (5). An earlier study reported ripples in waking and sleeping cat cortex, especially NREM (6). In humans, cortical ripples have recently been identified during waking and were more frequently found in lateral temporal than in rolandic cortex. Hippocampal sharpwave-ripple occurrence and ripple coupling between parahippocampal gyrus and temporal association cortex increase preceding memory recall in humans (7, 8), possibly facilitating replay of cortical neuron firing sequences established during encoding (9). In rats, ripples co-occur between hippocampus and ∼1 mm² of parietal cortex in sleep following learning (5), in mice, ripples propagate from the hippocampus to retrosplenial cortex (10), and in cats, ripple co-occurrence is reportedly limited to short distances (6).We recently reported, using human intracranial recordings, that ∼70-ms-long, ∼90-Hz ripples are ubiquitous in all regions of the cortex during NREM as well as waking (11). During waking, cortical ripples occur on local high-frequency activity peaks. During sleep, cortical ripples typically occur on the cortical down-to-upstate transition, often with 10- to 16-Hz cortical sleep spindles, and local unit firing patterns consistent with generation by pyramidal-interneuron feedback. We found that cortical ripples group cofiring within the window of spike-timing-dependent plasticity. These findings are consistent with cortical ripples contributing to memory consolidation during NREM in humans.While there is thus an emerging appreciation that hippocampal and cortical ripples have an important role in human and rodent memory, nothing is known of the network properties of cortical ripples. Specifically, it is not known if ripples co-occur or phase-synchronize between cortical sites and, if so, whether this is affected by distance or correlated with the reconstruction of declarative memories. These would be critical properties for cortical ripples to participate in the binding of different elements of memories that are represented in disparate cortical areas, the essence of hippocampus-dependent memory (12).The binding of disparate elements of a memory is a specific case of a more general problem of how the various contents of a mental event are united into a single experience. Most often addressed is how different visual qualities of an object (e.g., color, shape, location, and texture) are associated with each other (13), but the “binding problem” generalizes to how the contents of awareness are unified in a single stream of consciousness (14). Modern accounts often rely on hierarchical and multimodal convergence. However, cortical processing is distributed, and it would be difficult to represent the combinatorial possibilities contained in all potential experiences with convergence, leading to the suggestion that temporal synchrony binds cortical areas (15). This hypothesis was first supported by phase-locked unit firing and local field potentials (LFPs) at 40 to 60 Hz evoked by simple visual stimuli in the anesthetized cat primary visual cortex at distances <7 mm (16). Although some further studies found similar results in other cortical areas, behaviors, and species, as would be expected under the binding-by-synchrony hypothesis (17, 18), others have been less successful (19). Synchronous high-gamma oscillations have also been criticized as providing no mechanism for neuronal interaction beyond generic activation (19, 20).Here, using human intracranial stereoelectroencephalography (SEEG) recordings, we find that ripples co-occur and, remarkably, phase-synchronize across all lobes and between both hemispheres, with little decrement, even at long distances. Furthermore, ripple co-occurrence is enhanced between cortical sites as well as between the cortex and hippocampus preceding successful delayed recall. Corippling was progressively above that expected as it involved a larger proportion of sites, and this led to progressively stronger phase locking. Single-unit firing increased during, and phase-locked to, cortical ripples, providing a basic requirement for ripples to enhance communication via gain modulation and coincidence detection. Enhanced communication was supported by our finding of increased high-frequency correlation between even distant corippling regions. These characteristics suggest that distributed, phase-locked cortical ripples possess the properties that may allow them to help integrate different components of a memory. More generally, ripples may help to “bind” different aspects of a mental event encoded in widespread cortical areas into a coherent representation.