In rodents, waking firing patterns replay in NREM sleep during hippocampal sharpwave ripples (HC-SWRs), correlated with neocortical graphoelements (NC-GEs). NC-GEs include theta bursts, spindles, downstates, and upstates. In humans, consolidation during sleep is correlated with scalp-recorded spindles and downstates/upstates, but HC-SWRs cannot be recorded noninvasively. Here we show in humans of both sexes that HC-SWRs are highly correlated with NC-GEs during NREM, with significantly more related HC-SWRs/NC-GEs for downstates or upstates than theta bursts or spindles, in N2 than N3, in posterior than anterior HC, in frontal than occipital cortex, and ipsilaterally than contralaterally. The preferences interacted (e.g., frontal spindles co-occurred frequently with posterior HC-SWRs in N2). These preferred GEs, stages, and locations for HC-SWR/NC-GE interactions may index selective consolidation activity, although that was not tested in this study. SWR recorded in different HC regions seldom co-occurred, and were related to GE in different cortical areas, showing that HC-NC interact in multiple transient, widespread but discrete, networks. NC-GEs tend to occur with consistent temporal relationships to HC-SWRs, and to each other. Cortical theta bursts usually precede HC-SWRs, where they may help define cortical input triggering HC-SWR firing. HC-SWRs often follow cortical downstate onsets, surrounded by locally decreased broadband power, suggesting a mechanism synchronizing cortical, thalamic, and hippocampal activities. Widespread cortical upstates and spindles follow HC-SWRs, consistent with the hypothesized contribution by hippocampal firing during HC-SWRs to cortical firing-patterns during upstates and spindles. Overall, our results describe how hippocampal and cortical oscillations are coordinated in humans during events that are critical for memory consolidation in rodents.

Human anterior and posterior hippocampus (aHC, pHC) differ in connectivity and behavioral correlates. Here we report physiological differences in humans of both sexes. During NREM sleep, the human hippocampus generates sharpwave ripples (SWRs) similar to those which in rodents mark memory replay. We show that while pHC generates SWRs, it also generates approximately as many spindle ripples (SSR: ripples phase-locked to local spindles). In contrast, SSRs are rare in aHC. Like SWRs, SSRs often co-occur with neocortical theta bursts (TBs), downstates (DSs), sleep spindles (SSs), and upstates (USs), which coordinate cortico-hippocampal interactions and facilitate consolidation in rodents. SWRs co-occur with these waves in widespread cortical areas, especially frontocentral. These waves typically occur in the sequence TB-DS-SS-US, with SWRs usually occurring before SS-US. In contrast, SSRs occur ϳ350 ms later, with a strong preference for co-occurrence with posterior-parietal SSs. pHC-SSs were strongly phase-locked with parietal-SSs, and pHC-SSRs were phase-coupled with pHC-SSs and parietal-SSs. Human SWRs (and associated replay events, if any) are separated by ϳ5 s on average, whereas ripples on successive SSR peaks are separated by only ϳ80 ms. These distinctive physiological properties of pHC-SSR enable an alternative mechanism for hippocampal engagement with neocortex.

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.

Animal studies support the hypothesis that in slow-wave sleep, replay of waking neocortical activity under hippocampal guidance leads to memory consolidation. However, no intracranial electrophysiological evidence for replay exists in humans. We identified consistent sequences of population firing peaks across widespread cortical regions during complete waking periods. The occurrence of these “Motifs” were compared between sleeps preceding the waking period (“Sleep-Pre”) when the Motifs were identified, and those following (“Sleep-Post”). In all subjects, the majority of waking Motifs (most of which were novel) had more matches in Sleep-Post than in Sleep-Pre. In rodents, hippocampal replay occurs during local sharp-wave ripples, and the associated neocortical replay tends to occur during local sleep spindles and down-to-up transitions. These waves may facilitate consolidation by sequencing cell-firing and encouraging plasticity. Similarly, we found that Motifs were coupled to neocortical spindles, down-to-up transitions, theta bursts, and hippocampal sharp-wave ripples. While Motifs occurring during cognitive task performance were more likely to have more matches in subsequent sleep, our studies provide no direct demonstration that the replay of Motifs contributes to consolidation. Nonetheless, these results confirm a core prediction of the dominant neurobiological theory of human memory consolidation.

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 pyramidalinterneuron 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 prior to the upstate peak, often during spindles. Upstates and spindles have previously been associated with memory consolidation, and we found that cortical ripples grouped co-firing between units within the window of spike-timing-dependent plasticity. Thus, human NREM cortical ripples are: ubiquitous and stereotyped with a tightly focused oscillation frequency; similar to hippocampal ripples; associated with upstates and spindles; and associated with unit co-firing. These properties are consistent with cortical ripples possibly contributing to memory consolidation and other functions during NREM in humans. Significance StatementIn 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 anatomical 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.