Parp1 promotes sleep, which enhances DNA repair in neurons.

The characteristics of the sleep drivers and the mechanisms through which sleep relieves the cellular homeostatic pressure are unclear. In flies, zebrafish, mice, and humans, DNA damage levels increase during wakefulness and decrease during sleep. Here, we show that 6 h of consolidated sleep is sufficient to reduce DNA damage in the zebrafish dorsal pallium. Induction of DNA damage by neuronal activity and mutagens triggered sleep and DNA repair. The activity of the DNA damage response (DDR) proteins Rad52 and Ku80 increased during sleep, and chromosome dynamics enhanced Rad52 activity. The activity of the DDR initiator poly(ADP-ribose) polymerase 1 (Parp1) increased following sleep deprivation. In both larva zebrafish and adult mice, Parp1 promoted sleep. Inhibition of Parp1 activity reduced sleep-dependent chromosome dynamics and repair. These results demonstrate that DNA damage is a homeostatic driver for sleep, and Parp1 pathways can sense this cellular pressure and facilitate sleep and repair activity.

A bistable inhibitory optoGPCR for multiplexed optogenetic control of neural circuits.

Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein-coupled receptor pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumerilii ciliary opsin (PdCO) is an efficient, versatile, light-activated bistable G-protein-coupled receptor that can suppress synaptic transmission in mammalian neurons with high temporal precision in vivo. PdCO has useful biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping.

Pathological neurons generate ripples at the UP-DOWN transition disrupting information transfer.

OBJECTIVE: To confirm and investigate why pathological high-frequency oscillations (pHFOs), including ripples (80-200 Hz) and fast ripples (200-600 Hz), are generated during the UP-DOWN transition of the slow wave and if information transmission mediated by ripple temporal coupling is disrupted in the seizure-onset zone (SOZ). METHODS: We isolated 217 total units from 175.95 intracranial electroencephalography (iEEG) contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the SOZ, HFOs and associated action potentials (APs) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross-correlograms. RESULTS: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p < < .001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p < < .001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d = .11-.83) and fast ripples (d = .36-.90) at the UP-DOWN transition (p < .05 f.d.r. corrected), respectively. By comparison, also in the SOZ, 6.6% (d = .14-.30) and 8.5% (d = .33-.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows that ripple and fast ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by >50% in the SOZ compared to the non-SOZ (N = 3). SIGNIFICANCE: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. Ripple temporal correlations across brain regions may be important in memory consolidation and are disrupted in the SOZ, perhaps by pHFO generation.

A visual paired associate learning (vPAL) paradigm to study memory consolidation during sleep.

Sleep improves the consolidation and long-term stability of newly formed memories and associations. Most research on human declarative memory and its consolidation during sleep uses word-pair associations requiring exhaustive learning. In the present study, we present the visual paired association learning (vPAL) paradigm, in which participants learn new associations between images of celebrities and animals. The vPAL is based on a one-shot exposure that resembles learning in natural conditions. We tested if vPAL can reveal a role for sleep in memory consolidation by assessing the specificity of memory recognition, and the cued recall performance, before and after sleep. We found that a daytime nap improved the stability of recognition memory and discrimination abilities compared to identical intervals of wakefulness. By contrast, cued recall of associations did not exhibit significant sleep-dependent effects. High-density electroencephalography during naps further revealed an association between sleep spindle density and stability of recognition memory. Thus, the vPAL paradigm opens new avenues for future research on sleep and memory consolidation across ages and heterogeneous populations in health and disease.

Propofol anesthesia concentration rather than abrupt behavioral unresponsiveness linearly degrades responses in the rat primary auditory cortex.

Despite extensive knowledge of its molecular and cellular effects, how anesthesia affects sensory processing remains poorly understood. In particular, it remains unclear whether anesthesia modestly or robustly degrades activity in primary sensory regions, and whether such changes are linked to anesthesia drug concentration versus behavioral unresponsiveness, which are typically confounded. Here, we used slow gradual intravenous propofol anesthesia induction together with auditory stimulation and intermittent assessment of behavioral responsiveness while recording epidural electroencephalogram, and neuronal spiking activity in primary auditory cortex (PAC) of eight rats. We found that all main components of neuronal activity including spontaneous firing rates, onset response magnitudes, onset response latencies, postonset neuronal silence duration, late-locking to 40 Hz click-trains, and offset responses, gradually changed in a dose-dependent manner with increasing anesthesia levels without showing abrupt shifts around loss of righting reflex or other time-points. Thus, the dominant factor affecting PAC responses is the anesthesia drug concentration rather than any sudden, dichotomous behavioral state changes. Our findings explain a wide array of seemingly conflicting results in the literature that, depending on the precise definition of wakefulness (vigilant vs. drowsy) and anesthesia (light vs. deep/surgical), report a spectrum of effects in primary regions ranging from minimal to dramatic differences.

Anesthesia-induced loss of consciousness disrupts auditory responses beyond primary cortex.

Despite its ubiquitous use in medicine, and extensive knowledge of its molecular and cellular effects, how anesthesia induces loss of consciousness (LOC) and affects sensory processing remains poorly understood. Specifically, it is unclear whether anesthesia primarily disrupts thalamocortical relay or intercortical signaling. Here we recorded intracranial electroencephalogram (iEEG), local field potentials (LFPs), and single-unit activity in patients during wakefulness and light anesthesia. Propofol infusion was gradually increased while auditory stimuli were presented and patients responded to a target stimulus until they became unresponsive. We found widespread iEEG responses in association cortices during wakefulness, which were attenuated and restricted to auditory regions upon LOC. Neuronal spiking and LFP responses in primary auditory cortex (PAC) persisted after LOC, while responses in higher-order auditory regions were variable, with neuronal spiking largely attenuated. Gamma power induced by word stimuli increased after LOC while its frequency profile slowed, thus differing from local spiking activity. In summary, anesthesia-induced LOC disrupts auditory processing in association cortices while relatively sparing responses in PAC, opening new avenues for future research into mechanisms of LOC and the design of anesthetic monitoring devices.

Transcutaneous Vagus Nerve Stimulation in Humans Induces Pupil Dilation and Attenuates Alpha Oscillations.

Vagus nerve stimulation (VNS) is widely used to treat drug-resistant epilepsy and depression. While the precise mechanisms mediating its long-term therapeutic effects are not fully resolved, they likely involve locus coeruleus (LC) stimulation via the nucleus of the solitary tract, which receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline levels, whereas LC lesions suppress VNS therapeutic efficacy. Noninvasive transcutaneous VNS (tVNS) uses electrical stimulation that targets the auricular branch of the vagus nerve at the cymba conchae of the ear. However, the extent to which tVNS mimics VNS remains unclear. Here, we investigated the short-term effects of tVNS in healthy human male volunteers (n = 24), using high-density EEG and pupillometry during visual fixation at rest. We compared short (3.4 s) trials of tVNS to sham electrical stimulation at the earlobe (far from the vagus nerve branch) to control for somatosensory stimulation. Although tVNS and sham stimulation did not differ in subjective intensity ratings, tVNS led to robust pupil dilation (peaking 4-5 s after trial onset) that was significantly higher than following sham stimulation. We further quantified, using parallel factor analysis, how tVNS modulates idle occipital alpha (8-13Hz) activity identified in each participant. We found greater attenuation of alpha oscillations by tVNS than by sham stimulation. This demonstrates that tVNS reliably induces pupillary and EEG markers of arousal beyond the effects of somatosensory stimulation, thus supporting the hypothesis that tVNS elevates noradrenaline and other arousal-promoting neuromodulatory signaling, and mimics invasive VNS.SIGNIFICANCE STATEMENT Current noninvasive brain stimulation techniques are mostly confined to modulating cortical activity, as is typical with transcranial magnetic or transcranial direct/alternating current electrical stimulation. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to stimulate subcortical arousal-promoting nuclei, though previous studies yielded inconsistent results. Here we show that short (3.4 s) tVNS pulses in naive healthy male volunteers induced transient pupil dilation and attenuation of occipital alpha oscillations. These markers of brain arousal are in line with the established effects of invasive VNS on locus coeruleus-noradrenaline signaling, and support that tVNS mimics VNS. Therefore, tVNS can be used as a tool for studying how endogenous subcortical neuromodulatory signaling affects human cognition, including perception, attention, memory, and decision-making; and also for developing novel clinical applications.

Delta oscillation coupled propagating fast ripples precede epileptiform discharges in patients with focal epilepsy.

Epileptiform spikes are used to localize epileptogenic brain tissue. The mechanisms that spontaneously trigger epileptiform discharges are not yet elucidated. Pathological fast ripple (FR, 200-600 Hz) are biomarkers of epileptogenic brain, and we postulated that FR network interactions are involved in generating epileptiform spikes. Using macroelectrode stereo intracranial EEG (iEEG) recordings from a cohort of 46 patients we found that, in the seizure onset zone (SOZ), propagating FR were more often followed by an epileptiform spike, as compared with non-propagating FR (p < 0.05). Propagating FR had a distinct frequency and larger power (p < 1e-10) and were more strongly phase coupled to the peak of iEEG delta oscillation, which likely correspond with the DOWN states during non-REM sleep (p < 1e-8), than non-propagating FR. While FR propagation was rare, all FR occurred with the highest probability within +/- 400 msec of epileptiform spikes with superimposed high-frequency oscillations (p < 0.05). Thus, a sub-population of epileptiform spikes in the SOZ, are preceded by propagating FR that are coordinated by the DOWN state during non-REM sleep.

Sleep Differentially Affects Early and Late Neuronal Responses to Sounds in Auditory and Perirhinal Cortices.

A fundamental feature of sleep is reduced behavioral responsiveness to external events, but the extent of processing along sensory pathways remains poorly understood. While responses are comparable across wakefulness and sleep in auditory cortex (AC), neuronal activity in downstream regions remains unknown. Here we recorded spiking activity in 435 neuronal clusters evoked by acoustic stimuli in the perirhinal cortex (PRC) and in AC of freely behaving male rats across wakefulness and sleep. Neuronal responses in AC showed modest (∼10%) differences in response gain across vigilance states, replicating previous studies. By contrast, PRC neuronal responses were robustly attenuated by 47% and 36% during NREM sleep and REM sleep, respectively. Beyond the separation according to cortical region, response latency in each neuronal cluster was correlated with the degree of NREM sleep attenuation, such that late (>40 ms) responses in all monitored regions diminished during NREM sleep. The robust attenuation of late responses prevalent in PRC represents a novel neural correlate of sensory disconnection during sleep, opening new avenues for investigating the mediating mechanisms.SIGNIFICANCE STATEMENT Reduced behavioral responsiveness to sensory stimulation is at the core of sleep's definition, but it is still unclear how the sleeping brain responds differently to sensory stimuli. In the current study, we recorded neuronal spiking responses to sounds along the cortical processing hierarchy of rats during wakefulness and natural sleep. Responses in auditory cortex only showed modest changes during sleep, whereas sleep robustly attenuated the responses of neurons in high-level perirhinal cortex. We also found that, during NREM sleep, the response latency predicts the degree of sleep attenuation in individual neurons above and beyond their anatomical location. These results provide anatomical and temporal signatures of sensory disconnection during sleep and pave the way to understanding the underlying mechanisms.

Attenuated Fast Steady-State Visual Evoked Potentials During Human Sleep.

During sleep, external sensory events rarely elicit a behavioral response or affect perception. However, how sensory processing differs between wakefulness and sleep remains unclear. A major difficulty in this field stems from using brief auditory stimuli that often trigger nonspecific high-amplitude "K-complex" responses and complicate interpretation. To overcome this challenge, here we delivered periodic visual flicker stimulation across sleep and wakefulness while recording high-density electroencephalography (EEG) in humans. We found that onset responses can be separated from frequency-specific steady-state visual evoked potentials (SSVEPs) selectively observed over visual cortex. Sustained SSVEPs in response to fast (8/10 Hz) stimulation are substantially stronger in wakefulness than in both nonrapid eye movement (NREM) and REM sleep, whereas SSVEP responses to slow (3/5 Hz) stimulation are stronger in both NREM and REM sleep than in wakefulness. Despite wake-like spontaneous activity, responses in REM sleep were similar to those in NREM sleep and different than wakefulness, in accordance with perceptual disconnection during REM sleep. Finally, analysis of amplitude and phase in single trials revealed that stronger fast SSVEPs in wakefulness are driven by more consistent phase locking and increased induced power. These results suggest that the sleeping brain is unable to effectively synchronize large neuronal populations in response to rapid sensory stimulation.

Sleep Disrupts High-Level Speech Parsing Despite Significant Basic Auditory Processing.

The extent to which the sleeping brain processes sensory information remains unclear. This is particularly true for continuous and complex stimuli such as speech, in which information is organized into hierarchically embedded structures. Recently, novel metrics for assessing the neural representation of continuous speech have been developed using noninvasive brain recordings that have thus far only been tested during wakefulness. Here we investigated, for the first time, the sleeping brain's capacity to process continuous speech at different hierarchical levels using a newly developed Concurrent Hierarchical Tracking (CHT) approach that allows monitoring the neural representation and processing-depth of continuous speech online. Speech sequences were compiled with syllables, words, phrases, and sentences occurring at fixed time intervals such that different linguistic levels correspond to distinct frequencies. This enabled us to distinguish their neural signatures in brain activity. We compared the neural tracking of intelligible versus unintelligible (scrambled and foreign) speech across states of wakefulness and sleep using high-density EEG in humans. We found that neural tracking of stimulus acoustics was comparable across wakefulness and sleep and similar across all conditions regardless of speech intelligibility. In contrast, neural tracking of higher-order linguistic constructs (words, phrases, and sentences) was only observed for intelligible speech during wakefulness and could not be detected at all during nonrapid eye movement or rapid eye movement sleep. These results suggest that, whereas low-level auditory processing is relatively preserved during sleep, higher-level hierarchical linguistic parsing is severely disrupted, thereby revealing the capacity and limits of language processing during sleep.SIGNIFICANCE STATEMENT Despite the persistence of some sensory processing during sleep, it is unclear whether high-level cognitive processes such as speech parsing are also preserved. We used a novel approach for studying the depth of speech processing across wakefulness and sleep while tracking neuronal activity with EEG. We found that responses to the auditory sound stream remained intact; however, the sleeping brain did not show signs of hierarchical parsing of the continuous stream of syllables into words, phrases, and sentences. The results suggest that sleep imposes a functional barrier between basic sensory processing and high-level cognitive processing. This paradigm also holds promise for studying residual cognitive abilities in a wide array of unresponsive states.

Why Does Sleep Slow-Wave Activity Increase After Extended Wake? Assessing the Effects of Increased Cortical Firing During Wake and Sleep.

During non-rapid eye movement (NREM) sleep, cortical neurons alternate between ON periods of firing and OFF periods of silence. This bi-stability, which is largely synchronous across neurons, is reflected in the EEG as slow waves. Slow-wave activity (SWA) increases with wake duration and declines homeostatically during sleep, but the underlying mechanisms remain unclear. One possibility is neuronal "fatigue": high, sustained firing in wake would force neurons to recover with more frequent and longer OFF periods during sleep. Another possibility is net synaptic potentiation during wake: stronger coupling among neurons would lead to greater synchrony and therefore higher SWA. Here, we obtained a comparable increase in sustained firing (6 h) in cortex by: (1) keeping mice awake by exposure to novel objects to promote plasticity and (2) optogenetically activating a local population of cortical neurons at wake-like levels during sleep. Sleep after extended wake led to increased SWA, higher synchrony, and more time spent OFF, with a positive correlation between SWA, synchrony, and OFF periods. Moreover, time spent OFF was correlated with cortical firing during prior wake. After local optogenetic stimulation, SWA and cortical synchrony decreased locally, time spent OFF did not change, and local SWA was not correlated with either measure. Moreover, laser-induced cortical firing was not correlated with time spent OFF afterward. Overall, these results suggest that high sustained firing per se may not be the primary determinant of SWA increases observed after extended wake. SIGNIFICANCE STATEMENT: A long-standing hypothesis is that neurons fire less during slow-wave sleep to recover from the "fatigue" accrued during wake, when overall synaptic activity is higher than in sleep. This idea, however, has rarely been tested and other factors, namely increased cortical synchrony, could explain why sleep slow-wave activity (SWA) is higher after extended wake. We forced neurons in the mouse cortex to fire at high levels for 6 h in 2 different conditions: during active wake with exploration and during sleep. We find that neurons need more time OFF only after sustained firing in wake, suggesting that fatigue due to sustained firing alone is unlikely to account for the increase in SWA that follows sleep deprivation.

Local sleep in awake rats.

In an awake state, neurons in the cerebral cortex fire irregularly and electroencephalogram (EEG) recordings display low-amplitude, high-frequency fluctuations. During sleep, neurons oscillate between 'on' periods, when they fire as in an awake brain, and 'off' periods, when they stop firing altogether and the EEG displays high-amplitude slow waves. However, what happens to neuronal firing after a long period of being awake is not known. Here we show that in freely behaving rats after a long period in an awake state, cortical neurons can go briefly 'offline' as in sleep, accompanied by slow waves in the local EEG. Neurons often go offline in one cortical area but not in another, and during these periods of 'local sleep', the incidence of which increases with the duration of the awake state, rats are active and display an 'awake' EEG. However, they are progressively impaired in a sugar pellet reaching task. Thus, although both the EEG and behaviour indicate wakefulness, local populations of neurons in the cortex may be falling asleep, with negative consequences for performance.

Auditory responses and stimulus-specific adaptation in rat auditory cortex are preserved across NREM and REM sleep.

Sleep entails a disconnection from the external environment. By and large, sensory stimuli do not trigger behavioral responses and are not consciously perceived as they usually are in wakefulness. Traditionally, sleep disconnection was ascribed to a thalamic "gate," which would prevent signal propagation along ascending sensory pathways to primary cortical areas. Here, we compared single-unit and LFP responses in core auditory cortex as freely moving rats spontaneously switched between wakefulness and sleep states. Despite robust differences in baseline neuronal activity, both the selectivity and the magnitude of auditory-evoked responses were comparable across wakefulness, Nonrapid eye movement (NREM) and rapid eye movement (REM) sleep (pairwise differences <8% between states). The processing of deviant tones was also compared in sleep and wakefulness using an oddball paradigm. Robust stimulus-specific adaptation (SSA) was observed following the onset of repetitive tones, and the strength of SSA effects (13-20%) was comparable across vigilance states. Thus, responses in core auditory cortex are preserved across sleep states, suggesting that evoked activity in primary sensory cortices is driven by external physical stimuli with little modulation by vigilance state. We suggest that sensory disconnection during sleep occurs at a stage later than primary sensory areas.

Claustrum neurons projecting to the anterior cingulate restrict engagement during sleep and behavior.

The claustrum has been linked to attention and sleep. We hypothesized that this reflects a shared function, determining responsiveness to stimuli, which spans the axis of engagement. To test this hypothesis, we recorded claustrum population dynamics from male mice during both sleep and an attentional task ('ENGAGE'). Heightened activity in claustrum neurons projecting to the anterior cingulate cortex (ACCp) corresponded to reduced sensory responsiveness during sleep. Similarly, in the ENGAGE task, heightened ACCp activity correlated with disengagement and behavioral lapses, while low ACCp activity correlated with hyper-engagement and impulsive errors. Chemogenetic elevation of ACCp activity reduced both awakenings during sleep and impulsive errors in the ENGAGE task. Furthermore, mice employing an exploration strategy in the task showed a stronger correlation between ACCp activity and performance compared to mice employing an exploitation strategy which reduced task complexity. Our results implicate ACCp claustrum neurons in restricting engagement during sleep and goal-directed behavior.

Resting state functional connectivity reflects abnormal task-activated patterns in a developmental object agnosic.

Even in the absence of stimulation or task, the cerebral cortex shows an incessant pattern of ultra slow fluctuations which are coherent across brain regions. In the healthy brain these coherent patterns (also termed resting state functional connectivity) often exhibit spatial similarity to the large scale organization of task-induced functional networks. However, it is not clear to what extent the resting state patterns can also reflect task-induced abnormalities in cortical activations which are often detected in various brain pathologies. Here we examined whether an abnormal visual activation pattern is recapitulated in the resting state functional connectivity. We examined LG, a sighted young adult with developmental object agnosia and no apparent cortical structural abnormality. We have previously reported that upon visual stimulation, LG's intermediate visual areas (V2, V3) are paradoxically deactivated. Here, examining LG's resting state functional connectivity revealed the same pattern of functional abnormality - including a strong atypical decorrelation between areas V2-V3 and the rest of the visual system. Thus, our results suggest that resting-state functional connectivity could provide a powerful tool which could complement task-specific paradigms in detecting task-related abnormalities in cortical activity without resorting to task performance.

Sleep and vigilance states: Embracing spatiotemporal dynamics.

The classic view of sleep and vigilance states is a global stationary perspective driven by the interaction between neuromodulators and thalamocortical systems. However, recent data are challenging this view by demonstrating that vigilance states are highly dynamic and regionally complex. Spatially, sleep- and wake-like states often co-occur across distinct brain regions, as in unihemispheric sleep, local sleep in wakefulness, and during development. Temporally, dynamic switching prevails around state transitions, during extended wakefulness, and in fragmented sleep. This knowledge, together with methods monitoring brain activity across multiple regions simultaneously at millisecond resolution with cell-type specificity, is rapidly shifting how we consider vigilance states. A new perspective incorporating multiple spatial and temporal scales may have important implications for considering the governing neuromodulatory mechanisms, the functional roles of vigilance states, and their behavioral manifestations. A modular and dynamic view highlights novel avenues for finer spatiotemporal interventions to improve sleep function.

Sleep-like changes in neural processing emerge during sleep deprivation in early auditory cortex.

Insufficient sleep is commonplace in modern lifestyle and can lead to grave outcomes, yet the changes in neuronal activity accumulating over hours of extended wakefulness remain poorly understood. Specifically, which aspects of cortical processing are affected by sleep deprivation (SD), and whether they also affect early sensory regions, remain unclear. Here, we recorded spiking activity in the rat auditory cortex along with polysomnography while presenting sounds during SD followed by recovery sleep. We found that frequency tuning, onset responses, and spontaneous firing rates were largely unaffected by SD. By contrast, SD decreased entrainment to rapid (≥20 Hz) click trains, increased population synchrony, and increased the prevalence of sleep-like stimulus-induced silent periods, even when ongoing activity was similar. Recovery NREM sleep was associated with similar effects as SD with even greater magnitude, while auditory processing during REM sleep was similar to vigilant wakefulness. Our results show that processes akin to those in NREM sleep invade the activity of cortical circuits during SD, even in the early sensory cortex.

Pathological neurons generate ripples at the UP-DOWN transition disrupting information transfer.

Objective: To confirm and investigate why pathological HFOs (pHFOs), including Ripples [80-200 Hz] and fast ripples [200-600 Hz], are generated during the UP-DOWN transition of the slow wave and if pHFOs interfere with information transmission. Methods: We isolated 217 total units from 175.95 iEEG contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (0.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the seizure onset zone (SOZ), HFOs and associated action potentials (AP) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross correlograms. Results: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p<<0.001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p<<0.001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d=0.11-0.83) and fast ripples (d=0.36-0.90) at the UP-DOWN transition (p<0.05 f.d.r corrected), respectively. By comparison, also in the SOZ, 6.6% (d=0.14-0.30) and 8.5% (d=0.33-0.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by ~50-80% in the SOZ compared to the non-SOZ (N=3). Significance: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. The pathological neurons and pHFOs disrupt ripple temporal correlations across brain regions that transfer information and may be important in memory consolidation.

Augmenting hippocampal-prefrontal neuronal synchrony during sleep enhances memory consolidation in humans.

Memory consolidation during sleep is thought to depend on the coordinated interplay between cortical slow waves, thalamocortical sleep spindles and hippocampal ripples, but direct evidence is lacking. Here, we implemented real-time closed-loop deep brain stimulation in human prefrontal cortex during sleep and tested its effects on sleep electrophysiology and on overnight consolidation of declarative memory. Synchronizing the stimulation to the active phases of endogenous slow waves in the medial temporal lobe (MTL) enhanced sleep spindles, boosted locking of brain-wide neural spiking activity to MTL slow waves, and improved coupling between MTL ripples and thalamocortical oscillations. Furthermore, synchronized stimulation enhanced the accuracy of recognition memory. By contrast, identical stimulation without this precise time-locking was not associated with, and sometimes even degraded, these electrophysiological and behavioral effects. Notably, individual changes in memory accuracy were highly correlated with electrophysiological effects. Our results indicate that hippocampo-thalamocortical synchronization during sleep causally supports human memory consolidation.