Systems Consolidation Research Articles

Integration of overlapping sequences emerges with consolidation through medial prefrontal cortex neural ensembles and hippocampal-cortical connectivity.

Systems consolidation theories propose two mechanisms that enable the behavioral integration of related memories: coordinated reactivation between hippocampus and cortex, and the emergence of cortical traces that reflect overlap across memories. However, there is limited empirical evidence that links these mechanisms to the emergence of behavioral integration over time. In two experiments, participants implicitly encoded sequences of objects with overlapping structure. Assessment of behavioral integration showed that response times during a recognition task reflected behavioral priming between objects that never occurred together in time but belonged to overlapping sequences. This priming was consolidation-dependent and only emerged for sequences learned 24 hr prior to the test. Critically, behavioral integration was related to changes in neural pattern similarity in the medial prefrontal cortex and increases in post-learning rest connectivity between the posterior hippocampus and lateral occipital cortex. These findings suggest that memories with a shared predictive structure become behaviorally integrated through a consolidation-related restructuring of the learned sequences, providing insight into the relationship between different consolidation mechanisms that support behavioral integration.

Topography of putative bidirectional interaction between hippocampal sharp wave ripples and neocortical slow oscillations.

Systems consolidation relies on coordination between hippocampal sharp-wave ripples (SWRs) and neocortical UP/DOWN states during sleep. However, whether this coupling exists across neocortex and the mechanisms enabling it remain unknown. By combining electrophysiology in mouse hippocampus (HPC) and retrosplenial cortex (RSC) with widefield imaging of dorsal neocortex, we found spatially and temporally precise bidirectional hippocampo-neocortical interaction. HPC multi-unit activity and SWR probability was correlated with UP/DOWN states in mouse default mode network, with highest modulation by RSC in deep sleep. Further, some SWRs were preceded by the high rebound excitation accompanying DMN DOWN→UP transitions, while large-amplitude SWRs were often followed by DOWN states originating in RSC. We explain these electrophysiological results with a model in which HPC and RSC are weakly coupled excitable systems capable of bi-directional perturbation and suggest RSC may act as a gateway through which SWRs can perturb downstream cortical regions via cortico-cortical propagation of DOWN states.

Synaptic weight dynamics underlying memory consolidation: Implications for learning rules, circuit organization, and circuit function

Systems consolidation is a common feature of learning and memory systems, in which a long-term memory initially stored in one brain region becomes persistently stored in another region. We studied the dynamics of systems consolidation in simple circuit architectures with two sites of plasticity, one in an early-learning and one in a late-learning brain area. We show that the synaptic dynamics of the circuit during consolidation of an analog memory can be understood as a temporal integration process, by which transient changes in activity driven by plasticity in the early-learning area are accumulated into persistent synaptic changes at the late-learning site. This simple principle naturally leads to a speed-accuracy tradeoff in systems consolidation and provides insight into how the circuit mitigates the stability-plasticity dilemma of storing new memories while preserving core features of older ones. Furthermore, it imposes two constraints on the circuit. First, the plasticity rule at the late-learning site must stably support a continuum of possible outputs for a given input. We show that this is readily achieved by heterosynaptic but not standard Hebbian rules. Second, to turn off the consolidation process and prevent erroneous changes at the late-learning site, neural activity in the early-learning area must be reset to its baseline activity. We provide two biologically plausible implementations for this reset that propose functional roles in stabilizing consolidation for core elements of the cerebellar circuit.

Hippocampus supports long-term maintenance of language representations: Evidence of impaired collocation knowledge in amnesia

Traditional systems consolidation theories of memory suggest that the role of the hippocampus in maintaining memory representations diminishes over time, with learned information eventually becoming fully independent of the hippocampus. Knowledge of collocations in one’s native (L1) language are acquired during development and are solidly acquired by adulthood. Remote semantic knowledge of collocations might therefore be expected to be resistant to hippocampal pathology. Patients with hippocampal damage and severe anterograde amnesia completed two tasks testing English collocation knowledge originally designed for use with English language learners. Patients with hippocampal damage demonstrated impairments in recognition of common English collocations, despite a lifetime of language experience (including postsecondary education) prior to sustaining this damage. These results suggest the hippocampus contributes to the long-term maintenance of linguistic representations and provides a challenge to traditional consolidation views of memory and an extension of newer theories to include a role for the hippocampus in maintaining semantic memory.

Does sleep benefit source memory? Investigating 12-h retention intervals with a multinomial modeling approach.

For retention intervals of up to 12h, the active systems consolidation hypothesis predicts that sleep compared to wakefulness strengthens the context binding of memories previously established during encoding. Sleep should thus improve source memory. By comparing retention intervals filled with natural night sleep versus daytime wakefulness, we tested this prediction in two online source-monitoring experiments using intentionally learned pictures as items and incidentally learned screen positions and frame colors as source dimensions. In Experiment 1, we examined source memory by varying the spatial position of pictures on the computer screen. Multinomial modeling analyses revealed a significant sleep benefit in source memory. In Experiment 2, we manipulated both the spatial position and the frame color of pictures orthogonally to investigate source memory for two different source dimensions at the same time, also allowing exploration of bound memory for both source dimensions. The sleep benefit on spatial source memory replicated. In contrast, no source memory sleep benefit was observed for either frame color or bound memory of both source dimensions, probably as a consequence of a floor effect in incidental encoding of color associations. In sum, the results of both experiments show that sleep within a 12-h retention interval improves source memory for spatial positions, supporting the prediction of the active systems consolidation hypothesis. However, additional research is required to clarify the impact of sleep on source memory for other context features and bound memories of multiple source dimensions.

Memory consolidation affects the interplay of place and response navigation

Navigation through space is based on memory representations of landmarks (‘place’) or movement sequences (‘response’). Over time, memory representations transform through consolidation. However, it is unclear how the transformation affects place and response navigation in humans. In the present study, healthy adults navigated to target locations in a virtual maze. The preference for using place and response strategies and the ability to recall place and response memories were tested after a delay of one hour (n = 31), one day (n = 30), or two weeks (n = 32). The different delays captured early-phase synaptic changes, changes after one night of sleep, and long-delay changes due to the reorganization of navigation networks. Our results show that the relative contributions of place and response navigation changed as a function of time. After a short delay of up to one day, participants preferentially used a place strategy and exhibited a high degree of visual landmark exploration. After a longer delay of two weeks, place strategy use decreased significantly. Participants now equally relied on place and response strategy use and increasingly repeated previously taken paths. Further analyses indicate that response strategy use predominantly occurred as a compensatory strategy in the absence of sufficient place memory. Over time, place memory faded before response memory. We suggest that the observed shift from place to response navigation is context-dependent since detailed landmark information, which strongly relied on hippocampal function, decayed faster than sequence information, which required less detail and depended on extra-hippocampal areas. We conclude that changes in place and response navigation likely reflect the reorganization of navigation networks during systems consolidation.

An Enduring Role for Hippocampal Pattern Completion in Addition to an Emergent Nonhippocampal Contribution to Holistic Episodic Retrieval after a 24 h Delay.

Episodic memory retrieval is associated with the holistic neocortical reinstatement of all event information, an effect driven by hippocampal pattern completion. However, whether holistic reinstatement occurs, and whether hippocampal pattern completion continues to drive reinstatement, after a period of consolidation is unclear. Theories of systems consolidation predict either a time-variant or time-invariant role of the hippocampus in the holistic retrieval of episodic events. Here, we assessed whether episodic events continue to be reinstated holistically and whether hippocampal pattern completion continues to facilitate holistic reinstatement following a period of consolidation. Female and male human participants learned "events" that comprised multiple overlapping pairs of event elements (e.g., person-location, object-location, location-person). Importantly, encoding occurred either immediately before or 24 h before retrieval. Using fMRI during the retrieval of events, we show evidence for holistic reinstatement, as well as a correlation between reinstatement and hippocampal pattern completion, regardless of whether retrieval occurred immediately or 24 h after encoding. Thus, hippocampal pattern completion continues to contribute to holistic reinstatement after a delay. However, our results also revealed that some holistic reinstatement can occur without evidence for a corresponding signature of hippocampal pattern completion after a delay (but not immediately after encoding). We therefore show that hippocampal pattern completion, in addition to a nonhippocampal process, has a role in holistic reinstatement following a period of consolidation. Our results point to a consolidation process where the hippocampus and neocortex may work in an additive, rather than compensatory, manner to support episodic memory retrieval.

Remote memory in a Bayesian model of context fear conditioning (BaconREM).

Here, we propose a model of remote memory (BaconREM), which is an extension of a previously published Bayesian model of context fear learning (BACON) that accounts for many aspects of recently learned context fear. BaconREM simulates most known phenomenology of remote context fear as studied in rodents and makes new predictions. In particular, it predicts the well-known observation that fear that was conditioned to a recently encoded context becomes hippocampus-independent and shows much-enhanced generalization ("hyper-generalization") when systems consolidation occurs (i.e., when memory becomes remote). However, the model also predicts that there should be circumstances under which the generalizability of remote fear may not increase or even decrease. It also predicts the established finding that a "reminder" exposure to a feared context can abolish hyper-generalization while at the same time making remote fear again hippocampus-dependent. This observation has in the past been taken to suggest that reminders facilitate access to detail memory that remains permanently in the hippocampus even after systems consolidation is complete. However, the present model simulates this result even though it totally moves all the contextual memory that it retains to the neo-cortex when context fear becomes remote.

Human brain activity and functional connectivity associated with verbal long-term memory consolidation across 1 month.

Declarative memories are initially dependent on the hippocampus and become stabilized through the neural reorganization of connections between the medial temporal lobe and neocortex. The exact time-course of these neural changes is not well established, although time-dependent changes in retrieval-related brain function can be detected across relatively short time periods in humans (e.g., hours to months). In a study involving older adults with normal cognition (N = 24), we investigated changes in brain activity and functional connectivity associated with the long-term memory consolidation of verbal material over one month. Participants studied fact-like, three-word sentences at 1-month, 1-week, 1-day, and 1-hour intervals before a recognition memory test inside an MRI scanner. Old/new recognition with confidence ratings and response times were recorded. We examined whole-brain changes in retrieval-related brain activity, as well as functional connectivity of the hippocampus and ventromedial prefrontal cortex (vmPFC), as memories aged from 1 hour to 1 month. Secondary analyses minimized the effect of confounding factors affected by memory age (i.e., changes in confidence and response time or re-encoding of targets). Memory accuracy, confidence ratings, and response times changed with memory age. A memory age network was identified where retrieval-related brain activity in cortical regions increased or decreased as a function of memory age. Hippocampal brain activity in an anatomical region of interest decreased with memory age. Importantly, these changes in retrieval-related activity were not confounded with changes in activity related to concomitant changes in behavior or encoding. Exploratory analyses of vmPFC functional connectivity as a function of memory age revealed increased connectivity with the posterior parietal cortex, as well as with the vmPFC itself. In contrast, hippocampal functional connectivity with the vmPFC and orbitofrontal cortex decreased with memory age. The observed changes in retrieval-related brain activity and functional connectivity align with the predictions of standard systems consolidation theory. These results suggest that processes consistent with long-term memory consolidation can be identified over short time periods using fMRI, particularly for verbal material.

Multiple mechanisms of visual prediction as revealed by the timecourse of scene-object facilitation.

Not only semantic, but also recently learned arbitrary associations have the potential to facilitate visual processing in everyday life-for example, knowledge of a (moveable) object's location at a specific time may facilitate visual processing of that object. In our prior work, we showed that previewing a scene can facilitate processing of recently associated objects at the level of visual analysis (Smith and Federmeier in Journal of Cognitive Neuroscience, 32(5):783-803, 2020). In the current study, we assess how rapidly this facilitation unfolds by manipulating scene preview duration. We then compare our results to studies using well-learned object-scene associations in a first-pass assessment of whether systems consolidation might speed up high-level visual prediction. In two ERP experiments (N = 60), we had participants study categorically organized novel object-scene pairs in an explicit paired associate learning task. At test, we varied contextual pre-exposure duration, both between (200 vs. 2500 ms) and within subjects (0-2500 ms). We examined the N300, an event-related potential component linked to high-level visual processing of objects and scenes and found that N300 effects of scene congruity increase with longer scene previews, up to approximately 1-2 s. Similar results were obtained for response times and in a separate component-neutral ERP analysis of visual template matching. Our findings contrast with prior evidence that scenes can rapidly facilitate visual processing of commonly associated objects. This raises the possibility that systems consolidation might mediate different kinds of predictive processing with different temporal profiles.

The Role of Prefrontal Ensembles in Memory Across Time: Time-Dependent Transformations of Prefrontal Memory Ensembles.

The medial prefrontal cortex (mPFC) plays a critical role in recalling recent and remote fearful memories. Modern neuroscience techniques, such as projection-specific circuit manipulation and activity-dependent labeling, have illuminated how mPFC memory ensembles are reorganized over time. This chapter discusses the implications of new findings for traditional theories of memory, such as the systems consolidation theory and theories of memory engrams. It also examines the specific contributions of mPFC subregions, like the prelimbic and infralimbic cortices, in fear memory, highlighting how their distinct connections influence memory recall. Further, it elaborates on the cellular and molecular changes within the mPFC that support memory persistence and how these are influenced by interactions with the hippocampus. Ultimately, this chapter provides insights into how lasting memories are dynamically encoded in prefrontal circuits, arguing for a key role of memory ensembles that extend beyond strict definitions of the engram.

Emotional Value of Fear Memory and the Role of the Ventral Hippocampus in Systems Consolidation

Recent studies have explored the circuitry involving the ventral hippocampus (vHPC), the amygdala, and the prefrontal cortex, a pathway mainly activated to store contextual information efficiently. Lesions in the vHPC impair remote memory, but not in the short term. However, how the vHPC is affected by distinct memory strength or its role in systems consolidation has not yet been elucidated. Here, we investigated how distinct training intensities, with strong or weak contextual fear conditioning, affect activation of the dorsal hippocampus (dHPC) and the vHPC. We found that the time course of memory consolidation differs in fear memories of different training intensities in both the dHPC and vHPC. Our results also indicate that memory generalization happens alongside greater activation of the vHPC, and these processes occur faster with stronger fear memories. The vHPC is required for the expression of remote fear memory and may control contextual fear generalization, a view corroborated by the fact that inactivation of the vHPC suppresses generalized fear expression, making memory more precise again. Systems consolidation occurs concomitantly with greater activation of the vHPC, which is accelerated in stronger fear memories. These findings lead us to propose that greater activation of the vHPC could be used as a marker for memory generalization.

Pre- and postsynaptic N-methyl-D-aspartate receptors are required for sequential printing of fear memory engrams

The organization of fear memory involves the participation of multiple brain regions. However, it is largely unknown how fear memory is formed, which circuit pathways are used for "printing" memory engrams across brain regions, and the role of identified brain circuits in memory retrieval. With advanced genetic methods, we combinatorially blocked presynaptic output and manipulated N-methyl-D-aspartate receptor (NMDAR) in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) before and after cued fear conditioning. Further, we tagged fear-activated neurons during associative learning for optogenetic memory recall. We found that presynaptic mPFC and postsynaptic BLA NMDARs are required for fear memory formation, but not expression. Our results provide strong evidence that NMDAR-dependent synaptic plasticity drives multi-trace systems consolidation for the sequential printing of fear memory engrams from BLA to mPFC and, subsequently, to the other regions, for flexible memory retrieval.

Awake Hippocampal-Cortical Co-reactivation Is Associated with Forgetting.

Systems consolidation theories posit that consolidation occurs primarily through a coordinated communication between hippocampus and neocortex [Moscovitch, M., & Gilboa, A. Systems consolidation, transformation and reorganization: Multiple trace theory, trace transformation theory and their competitors. PsyArXiv, 2021; Kumaran, D., Hassabis, D., & McClelland, J. L. What learning systems do intelligent agents need? Complementary learning systems theory updated. Trends in Cognitive Sciences, 20, 512-534, 2016; McClelland, J. L., & O'Reilly, R. C. Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychological Review, 102, 419-457, 1995]. Recent sleep studies in rodents have shown that hippocampus and visual cortex replay the same information at temporal proximity ("co-replay"; Lansink, C. S., Goltstein, P. M., Lankelma, J. V., McNaughton, B. L., & Pennartz, C. M. A. Hippocampus leads ventral striatum in replay of place-reward information. PLoS Biology, 7, e1000173, 2009; Peyrache, A., Khamassi, M., Benchenane, K., Wiener, S. I., & Battaglia, F. P. Replay of rule-learning related neural patterns in the prefrontal cortex during sleep. Nature Neuroscience, 12, 919-926, 2009; Wierzynski, C. M., Lubenov, E. V., Gu, M., & Siapas, A. G. State-dependent spike-timing relationships between hippocampal and prefrontal circuits during sleep. Neuron, 61, 587-596, 2009; Ji, D., & Wilson, M. A. Coordinated memory replay in the visual cortex and hippocampus during sleep. Nature Neuroscience, 10, 100-107, 2007). We developed a novel repetition time (TR)-based co-reactivation analysis method to study hippocampal-cortical co-replays in humans using fMRI. Thirty-six young adults completed an image (face or scene) and location paired associate encoding task in the scanner, which were preceded and followed by resting state scans. We identified post-encoding rest TRs (± 1) that showed neural reactivation of each image-location trials in both hippocampus (HPC) and category-selective cortex (fusiform face area [FFA]). This allowed us to characterize temporally proximal coordinated reactivations ("co-reactivations") between HPC and FFA. Moreover, we found that increased HPC-FFA co-reactivations were associated with incorrectly recognized trials after a 1-week delay (p = .004). Finally, we found that these HPC-FFA co-reactivations were also associated with trials that were initially correctly recognized immediately after encoding but were later forgotten in 1-day (p = .043) and 1-week delay period (p = .031). We discuss these results from a trace transformation perspective [Sekeres, M. J., Winocur, G., & Moscovitch, M. The hippocampus and related neocortical structures in memory transformation. Neuroscience Letters, 680, 39-53, 2018; Winocur, G., & Moscovitch, M. Memory transformation and systems consolidation. Journal of the International Neuropsychological Society, 17, 766-780, 2011] and speculate that HPC-FFA co-reactivations may be integrating related events, at the expense of disrupting event-specific details, hence leading to forgetting.

Engram stability and maturation during systems consolidation

Remote memories play an important role in how we perceive the world, and they are rooted throughout the brain in "engrams": ensembles of cells that are formed during acquisition. Upon their reactivation, a specific memory can be recalled.1,2,3,4,5,6,7,8,9,10,11,12 Many studies have focused on the ensembles in CA1 of the hippocampus and the anterior cingulate cortex (ACC). However, the evolution of these components during systems' consolidation has not yet been comprehensively addressed.13,14,15,16 By applying transgenic approaches for ensemble identification, CLARITY, retro-AAV, and pseudo-rabies virus for circuit mapping, and chemogenetics for functional interrogation, we addressed the dynamics of recent and remote CA1 ensembles. We expected both stability (as they represent the same memory) and maturation (over time). Indeed, we found that CA1 engrams remain stable between recent and remote recalls, and the inhibition of engrams for recent recall during remote recall functionally impairs memory. We also found that new cells in the remote recall engram in the CA1 are not added randomly during maturation but differ according to their connections. First, we show in two ways that the anterograde CA1 → ACC engram cell projection grows larger. Finally, in the retrograde projections, the ACC reduces input to CA1 engram cells, whereas input from the entorhinal cortex and paraventricular nucleus of the thalamus increases. Our results shine fresh light on systems' consolidation by providing a deeper understanding of engram stability and maturation in the transition from recent to remote memory.

Differential involvement of the anterior and posterior hippocampus, parahippocampus, and retrosplenial cortex in making precise judgments of spatial distance and object size for remotely acquired memories of environments and objects.

The hippocampus is known to support processing of precise spatial information in recently learned environments. It is less clear, but crucial for theories of systems consolidation, to know whether it also supports processing of precise spatial information in familiar environments learned long ago and whether such precision extends to objects and numbers. In this fMRI study, we asked participants to make progressively more refined spatial distance judgments among well-known Toronto landmarks (whether landmark A is closer to landmark B or C) to examine hippocampal involvement. We also tested whether the hippocampus was similarly engaged in estimating magnitude regarding sizes of familiar animals and numbers. We found that the hippocampus was only engaged in spatial judgment. Activation was greater and lasted longer in the posterior than anterior hippocampus, which instead showed greater modulation as discrimination between spatial distances became more fine grained. These findings suggest that the anterior and posterior hippocampus have different functions which are influenced differently by estimation of differential distance. Similarly, parahippocampal-place-area and retrosplenial cortex were involved only in the spatial condition. By contrast, activation of the intraparietal sulcus was modulated by precision in all conditions. Therefore, our study supports the idea that the hippocampus and related structures are implicated in retrieving and operating even on remote spatial memories whenever precision is required, as posted by some theories of systems consolidation.

Organizing memories for generalization in complementary learning systems

Memorization and generalization are complementary cognitive processes that jointly promote adaptive behavior. For example, animals should memorize safe routes to specific water sources and generalize from these memories to discover environmental features that predict new ones. These functions depend on systems consolidation mechanisms that construct neocortical memory traces from hippocampal precursors, but why systems consolidation only applies to a subset of hippocampal memories is unclear. Here we introduce a new neural network formalization of systems consolidation that reveals an overlooked tension—unregulated neocortical memory transfer can cause overfitting and harm generalization in an unpredictable world. We resolve this tension by postulating that memories only consolidate when it aids generalization. This framework accounts for partial hippocampal–cortical memory transfer and provides a normative principle for reconceptualizing numerous observations in the field. Generalization-optimized systems consolidation thus provides new insight into how adaptive behavior benefits from complementary learning systems specialized for memorization and generalization.

How coupled slow oscillations, spindles and ripples coordinate neuronal processing and communication during human sleep

Learning and plasticity rely on fine-tuned regulation of neuronal circuits during offline periods. An unresolved puzzle is how the sleeping brain, in the absence of external stimulation or conscious effort, coordinates neuronal firing rates (FRs) and communication within and across circuits to support synaptic and systems consolidation. Using intracranial electroencephalography combined with multiunit activity recordings from the human hippocampus and surrounding medial temporal lobe (MTL) areas, we show that, governed by slow oscillation (SO) up-states, sleep spindles set a timeframe for ripples to occur. This sequential coupling leads to a stepwise increase in (1) neuronal FRs, (2) short-latency cross-correlations among local neuronal assemblies and (3) cross-regional MTL interactions. Triggered by SOs and spindles, ripples thus establish optimal conditions for spike-timing-dependent plasticity and systems consolidation. These results unveil how the sequential coupling of specific sleep rhythms orchestrates neuronal processing and communication during human sleep.

Systems consolidation induces multiple memory engrams for a flexible recall strategy in observational fear memory in male mice

Observers learn to fear the context in which they witnessed a demonstrator’s aversive experience, called observational contextual fear conditioning (CFC). The neural mechanisms governing whether recall of the observational CFC memory occurs from the observer’s own or from the demonstrator’s point of view remain unclear. Here, we show in male mice that recent observational CFC memory is recalled in the observer’s context only, but remote memory is recalled in both observer and demonstrator contexts. Recall of recent memory in the observer’s context requires dorsal hippocampus activity, while recall of remote memory in both contexts requires the medial prefrontal cortex (mPFC)-basolateral amygdala pathway. Although mPFC neurons activated by observational CFC are involved in remote recall in both contexts, distinct mPFC subpopulations regulate remote recall in each context. Our data provide insights into a flexible recall strategy and the functional reorganization of circuits and memory engram cells underlying observational CFC memory.

0060 A Classification Based Generative Approach to Selective Targeting of Global Slow Oscillations during Sleep

Abstract Introduction Interacting with sleep slow oscillations (0.5,15 Hz) is essential to understanding the mechanisms underlying their role in sleep functions, including homeostasis, synaptic reorganization, and memory consolidation. Current approaches to SO-based non-invasive closed loop alternate current stimulation (cl-tACs) focus on timing, and do not differentiate among oscillations based on their space-time profiles. In this study, we leverage machine learning and global optimization to introduce a generative model of brain stimulation protocols targeting Global SOs. Methods We identify a stimulation protocol that matches a Global SO in two stages: first focusing on the electrode montage, and then on the stimulation waveform. Using the sleep night of 22 volunteers acquired in the lab with high density EEG (175 electrodes), we labeled the SOs as Global/non-Global SOs based on their co-detection on the scalp at a small delay (0.4s). We used the current density (CSD) profile of each SO in cortical and subcortical regions to develop a well-trained classifier (based on weighted k-nearest neighbors). We identify as optimal the electrode montage that resulted in CSDs labeled as Global with highest likelihood by the classifier. We then parameterized a sinusoidal waveform and identified optimum parameters with a genetic algorithm that used feature ranking to establish a weighted distance metric to target Global SO profile built from sleep data. We repeat this approach focusing on Global SO dynamics at a slow time scale and a faster time scale (200ms vs 20ms resolution). Results We identified optimal stimulation profiles matching Global SOs at both time scales. At slow time scale, montage selection relied only on CSD near the SO trough and in the reward network and the brainstem. Linear waveforms over-performed sinusoidal waveforms for fit at low time scales. At fast time scale, CSD at both trough and 500ms before the trough were strongly selective for Global vs. non-Global SO. Conclusion Global SOs are a gating mechanism for large-scale neural communication, a necessary substrate for systems consolidation and long-term memory formation. This data-driven method builds on natural sleep data to shape a stimulation protocol that imitates Global SO dynamics and is generalizable to other SO types. Support (if any)