Cortical Ripples during NREM Sleep and Waking in Humans

Abstract

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.

Thalamic spindles and upstates, but not ripples, coordinate cortico-cortical and hippocampo-cortical co-ripples in humans

“…The mechanism whereby thalamic spindles and upstates may help trigger cortical ripples could be through depolarizing cortical neurons for ~50-100 ms. Evidence for such depolarizations during NREM has been found in the prominent current sinks and large increases in both pyramidal and interneuron firing in microelectrode array recordings from human cortex during upstates and spindles (Cash et al, 2009; Csercsa et al, 2010; Dickey et al, 2022a; Hagler et al, 2018). Rodent hippocampal ripples can be induced by such broad ~60 ms duration depolarizing pulses, via a mechanism involving pyramidal-basket cell feedback loops (‘PING’) synchronized by basket–basket cell co-firing (‘ING’) (Stark et al, 2014).…”

“…Rodent hippocampal ripples can be induced by such broad ~60 ms duration depolarizing pulses, via a mechanism involving pyramidal-basket cell feedback loops (‘PING’) synchronized by basket–basket cell co-firing (‘ING’) (Stark et al, 2014). Further evidence that this mechanism is engaged in human cortical ripples during NREM is that they are accompanied by large increases in firing phase-locked to ripple oscillations, with pyramidal cells leading interneurons (Dickey et al, 2022a).…”

“…Ripples were detected in the thalamus, cortex, and hippocampus based on previously published methods (Dickey et al, 2022a;Dickey et al, 2022b). For each channel, data were bandpassed at 70-100 Hz with a 6 th order forward-reverse Butterworth filter (zero-phase shift) and peaks in the analytic amplitude of the Hilbert transform were selected if they were at least 3 standard deviations above the channel mean.…”

“…Timing relationships between ripples and other sleep waves were computed as previously described (Dickey et al, 2022a). Times of ripple centers relative to spindle onsets, downstate peaks, and upstate peaks on the same channel were determined for each channel.…”

“…In the rodent hippocampus during non-rapid eye movement sleep (NREM), ripples mark the replay of spatiotemporal firing patterns that play a crucial role in the consolidation of declarative memories (Buzsáki, 2015; Ego-Stengel and Wilson, 2009; Maingret et al, 2016; Wilson and McNaughton, 1994). In humans, ~70 ms long 90 Hz ripples are generated in the cortex during both NREM and waking (Dickey et al, 2022a; Dickey et al, 2022b). Cortical ripples couple to cortical and hippocampal ripples preceding recall (Dickey et al, 2022b; Vaz et al, 2019), when they entrain the replay of neuron firing sequences established during encoding (Vaz et al, 2020).…”