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.

Cortical Ripples during NREM Sleep and Waking in Humans.

Hippocampal ripples index the reconstruction of spatiotemporal neuronal firing patterns essential for the consolidation of memories in the cortex during non-rapid eye movement sleep (NREM). Recently, cortical ripples in humans have been shown to enfold the replay of neuron firing patterns during cued recall. Here, using intracranial recordings from 18 patients (12 female), we show that cortical ripples also occur during NREM in humans, with similar density, oscillation frequency (∼90 Hz), duration, and amplitude to waking. Ripples occurred in all cortical regions with similar characteristics, unrelated to putative hippocampal connectivity, and were less dense and robust in higher association areas. Putative pyramidal and interneuron spiking phase-locked to cortical ripples during NREM, with phase delays consistent with ripple generation through pyramidal-interneuron feedback. Cortical ripples were smaller in amplitude than hippocampal ripples but were similar in density, frequency, and duration. Cortical ripples during NREM typically occurred just before the upstate peak, often during spindles. Upstates and spindles have previously been associated with memory consolidation, and we found that cortical ripples grouped cofiring between units within the window of spike timing-dependent plasticity. Thus, human NREM cortical ripples are as follows: ubiquitous and stereotyped with a tightly focused oscillation frequency; similar to hippocampal ripples; associated with upstates and spindles; and associated with unit cofiring. These properties are consistent with cortical ripples possibly contributing to memory consolidation and other functions during NREM in humans.SIGNIFICANCE STATEMENT In rodents, hippocampal ripples organize replay during sleep to promote memory consolidation in the cortex, where ripples also occur. However, evidence for cortical ripples in human sleep is limited, and their anatomic distribution and physiological properties are unexplored. Here, using human intracranial recordings, we demonstrate that ripples occur throughout the cortex during waking and sleep with highly stereotyped characteristics. During sleep, cortical ripples tend to occur during spindles on the down-to-upstate transition, and thus participate in a sequence of sleep waves that is important for consolidation. Furthermore, cortical ripples organize single-unit spiking with timing optimal to facilitate plasticity. Therefore, cortical ripples in humans possess essential physiological properties to support memory and other cognitive functions.

Modular Phoneme Processing in Human Superior Temporal Gyrus.

Modular organization is fundamental to cortical processing, but its presence is human association cortex is unknown. We characterized phoneme processing with 128-1024 channel micro-arrays at 50-200µm pitch on superior temporal gyrus of 7 patients. High gamma responses were highly correlated within ~1.7mm diameter modules, sharply delineated from adjacent modules with distinct time-courses and phoneme-selectivity. We suggest that receptive language cortex may be organized in discrete processing modules.

Travelling spindles create necessary conditions for spike-timing-dependent plasticity in humans.

Sleep spindles facilitate memory consolidation in the cortex during mammalian non-rapid eye movement sleep. In rodents, phase-locked firing during spindles may facilitate spike-timing-dependent plasticity by grouping pre-then-post-synaptic cell firing within ~25 ms. Currently, microphysiological evidence in humans for conditions conducive for spike-timing-dependent plasticity during spindles is absent. Here, we analyze field potentials and unit firing from middle/upper layers during spindles from 10 × 10 microelectrode arrays at 400 µm pitch in humans. We report strong tonic and phase-locked increases in firing and co-firing within 25 ms during spindles, especially those co-occurring with down-to-upstate transitions. Co-firing, spindle co-occurrence, and spindle coherence are greatest within ~2 mm, and high co-firing of units on different contacts depends on high spindle coherence between those contacts. Spindles propagate at ~0.28 m/s in distinct patterns, with correlated cell co-firing sequences. Spindles hence organize spatiotemporal patterns of neuronal co-firing in ways that may provide pre-conditions for plasticity during non-rapid eye movement sleep.