Neuromodulatory effects on synchrony and network reorganization in networks of coupled Kuramoto oscillators.

Neuromodulatory processes in the brain can critically change signal processing on a cellular level leading to dramatic changes in network level reorganization. Here, we use coupled non-identical Kuramoto oscillators to investigate how changes in the shape of phase response curves from Type 1 to Type 2, mediated by varying ACh levels, coupled with activity dependent plasticity may alter network reorganization. We first show that when plasticity is absent, the Type 1 networks, as expected, exhibit asynchronous dynamics with oscillators of the highest natural frequency robustly evolving faster in terms of their phase dynamics. At the same time, the Type 2 networks synchronize, with oscillators locked so that the ones with higher natural frequency have a constant phase lead as compared to the ones with lower natural frequency. This relationship establishes a robust mapping between the frequency and oscillators' phases in the network, leading to structure/frequency mapping when plasticity is present. Further we show that while connection plasticity can produce stable synchrony (so called splay states) in Type 1 networks, the structure/frequency reorganization observed in Type 2 networks is not present.

High frequency oscillation network dynamics predict outcome in non-palliative epilepsy surgery.

High frequency oscillations are a promising biomarker of outcome in intractable epilepsy. Prior high frequency oscillation work focused on counting high frequency oscillations on individual channels, and it is still unclear how to translate those results into clinical care. We show that high frequency oscillations arise as network discharges that have valuable properties as predictive biomarkers. Here, we develop a tool to predict patient outcome before surgical resection is performed, based on only prospective information. In addition to determining high frequency oscillation rate on every channel, we performed a correlational analysis to evaluate the functional connectivity of high frequency oscillations in 28 patients with intracranial electrodes. We found that high frequency oscillations were often not solitary events on a single channel, but part of a local network discharge. Eigenvector and outcloseness centrality were used to rank channel importance within the connectivity network, then used to compare patient outcome by comparison with the seizure onset zone or a proportion within the proposed resected channels (critical resection percentage). Combining the knowledge of each patient's seizure onset zone resection plan along with our computed high frequency oscillation network centralities and high frequency oscillation rate, we develop a Naïve Bayes model that predicts outcome (positive predictive value: 100%) better than predicting based upon fully resecting the seizure onset zone (positive predictive value: 71%). Surgical margins had a large effect on outcomes: non-palliative patients in whom most of the seizure onset zone was resected ('definitive surgery', ≥ 80% resected) had predictable outcomes, whereas palliative surgeries (<80% resected) were not predictable. These results suggest that the addition of network properties of high frequency oscillations is more accurate in predicting patient outcome than seizure onset zone alone in patients with most of the seizure onset zone removed and offer great promise for informing clinical decisions in surgery for refractory epilepsy.

Neuromodulation via muscarinic acetylcholine pathway can facilitate distinct, complementary, and sequential roles for NREM and REM states during sleep-dependent memory consolidation.

Across vertebrate species, sleep consists of repeating cycles of NREM followed by REM. However, the respective functions of NREM, REM, and their stereotypic cycling pattern are not well understood. Using a simplified biophysical network model, we show that NREM and REM sleep can play differential and critical roles in memory consolidation primarily regulated, based on state-specific changes in cholinergic signaling. Within this network, decreasing and increasing muscarinic acetylcholine (ACh) signaling during bouts of NREM and REM, respectively, differentially alters neuronal excitability and excitatory/inhibitory balance. During NREM, deactivation of inhibitory neurons leads to network-wide disinhibition and bursts of synchronized activity led by firing in engram neurons. These features strengthen connections from the original engram neurons to less-active network neurons. In contrast, during REM, an increase in network inhibition suppresses firing in all but the most-active excitatory neurons, leading to competitive strengthening/pruning of the memory trace. We tested the predictions of the model against in vivo recordings from mouse hippocampus during active sleep-dependent memory storage. Consistent with modeling results, we find that functional connectivity between CA1 neurons changes differentially at transition from NREM to REM sleep during learning. Returning to the model, we find that an iterative sequence of state-specific activations during NREM/REM cycling is essential for memory storage in the network, serving a critical role during simultaneous consolidation of multiple memories. Together these results provide a testable mechanistic hypothesis for the respective roles of NREM and REM sleep, and their universal relative timing, in memory consolidation. Significance statement: Using a simplified computational model and in vivo recordings from mouse hippocampus, we show that NREM and REM sleep can play differential roles in memory consolidation. The specific neurophysiological features of the two sleep states allow for expansion of memory traces (during NREM) and prevention of overlap between different memory traces (during REM). These features are likely essential in the context of storing more than one new memory simultaneously within a brain network.

Acetylcholine facilitates localized synaptic potentiation and location specific feature binding.

Forebrain acetylcholine (ACh) signaling has been shown to drive attention and learning. Recent experimental evidence of spatially and temporally constrained cholinergic signaling has sparked interest to investigate how it facilitates stimulus-induced learning. We use biophysical excitatory-inhibitory (E-I) multi-module neural network models to show that external stimuli and ACh signaling can mediate spatially constrained synaptic potentiation patterns. The effects of ACh on neural excitability are simulated by varying the conductance of a muscarinic receptor-regulated hyperpolarizing slow K+ current (m-current). Each network module consists of an E-I network with local excitatory connectivity and global inhibitory connectivity. The modules are interconnected with plastic excitatory synaptic connections, that change via a spike-timing-dependent plasticity (STDP) rule. Our results indicate that spatially constrained ACh release influences the information flow represented by network dynamics resulting in selective reorganization of inter-module interactions. Moreover the information flow depends on the level of synchrony in the network. For highly synchronous networks, the more excitable module leads firing in the less excitable one resulting in strengthening of the outgoing connections from the former and weakening of its incoming synapses. For networks with more noisy firing patterns, activity in high ACh regions is prone to induce feedback firing of synchronous volleys and thus strengthening of the incoming synapses to the more excitable region and weakening of outgoing synapses. Overall, these results suggest that spatially and directionally specific plasticity patterns, as are presumed necessary for feature binding, can be mediated by spatially constrained ACh release.

Modeling cortical synaptic effects of anesthesia and their cholinergic reversal.

General anesthetics work through a variety of molecular mechanisms while resulting in the common end point of sedation and loss of consciousness. Generally, the administration of common anesthetics induces reduction in synaptic excitation while promoting synaptic inhibition. Exogenous modulation of the anesthetics' synaptic effects can help determine the neuronal pathways involved in anesthesia. For example, both animal and human studies have shown that exogenously induced increases in acetylcholine in the brain can elicit wakeful-like behavior despite the continued presence of the anesthetic. However, the underlying mechanisms of anesthesia reversal at the cellular level have not been investigated. Here we apply a computational model of a network of excitatory and inhibitory neurons to simulate the network-wide effects of anesthesia, due to changes in synaptic inhibition and excitation, and their reversal by cholinergic activation through muscarinic receptors. We use a differential evolution algorithm to fit model parameters to match measures of spiking activity, neuronal connectivity, and network dynamics recorded in the visual cortex of rodents during anesthesia with desflurane in vivo. We find that facilitating muscarinic receptor effects of acetylcholine on top of anesthetic-induced synaptic changes predicts the reversal of anesthetic suppression of neurons' spiking activity, functional connectivity, as well as pairwise and population interactions. Thus, our model predicts a specific neuronal mechanism for the cholinergic reversal of anesthesia consistent with experimental behavioral observations.

Binaural Processing Deficits Due to Synaptopathy and Myelin Defects.

Hidden hearing loss (HHL) is a deficit in auditory perception and speech intelligibility that occurs despite normal audiometric thresholds and results from noise exposure, aging, or myelin defects. While mechanisms causing perceptual deficits in HHL patients are still unknown, results from animal models indicate a role for peripheral auditory neuropathies in HHL. In humans, sound localization is particularly important for comprehending speech, especially in noisy environments, and its disruption may contribute to HHL. In this study, we hypothesized that neuropathies of cochlear spiral ganglion neurons (SGNs) that are observed in animal models of HHL disrupt the activity of neurons in the medial superior olive (MSO), a nucleus in the brainstem responsible for locating low-frequency sound in the horizontal plane using binaural temporal cues, leading to sound localization deficits. To test our hypothesis, we constructed a network model of the auditory processing system that simulates peripheral responses to sound stimuli and propagation of responses via SGNs to cochlear nuclei and MSO populations. To simulate peripheral auditory neuropathies, we used a previously developed biophysical SGN model with myelin defects at SGN heminodes (myelinopathy) and with loss of inner hair cell-SGN synapses (synaptopathy). Model results indicate that myelinopathy and synaptopathy in SGNs give rise to decreased interaural time difference (ITD) sensitivity of MSO cells, suggesting a possible mechanism for perceptual deficits in HHL patients. This model may be useful to understand downstream impacts of SGN-mediated disruptions on auditory processing and to eventually discover possible treatments for various mechanisms of HHL.

Heterogeneous mechanisms for synchronization of networks of resonant neurons under different E/I balance regimes.

Rhythmic synchronization of neuronal firing patterns is a widely present phenomenon in the brain-one that seems to be essential for many cognitive processes. A variety of mechanisms contribute to generation and synchronization of network oscillations, ranging from intrinsic cellular excitability to network mediated effects. However, it is unclear how these mechanisms interact together. Here, using computational modeling of excitatory-inhibitory neural networks, we show that different synchronization mechanisms dominate network dynamics at different levels of excitation and inhibition (i.e. E/I levels) as synaptic strength is systematically varied. Our results show that with low synaptic strength networks are sensitive to external oscillatory drive as a synchronizing mechanism-a hallmark of resonance. In contrast, in a strongly-connected regime, synchronization is driven by network effects via the direct interaction between excitation and inhibition, and spontaneous oscillations and cross-frequency coupling emerge. Unexpectedly, we find that while excitation dominates network synchrony at low excitatory coupling strengths, inhibition dominates at high excitatory coupling strengths. Together, our results provide novel insights into the oscillatory modulation of firing patterns in different excitation/inhibition regimes.

Acetylcholine-gated current translates wake neuronal firing rate information into a spike timing-based code in Non-REM sleep, stabilizing neural network dynamics during memory consolidation.

Sleep is critical for memory consolidation, although the exact mechanisms mediating this process are unknown. Combining reduced network models and analysis of in vivo recordings, we tested the hypothesis that neuromodulatory changes in acetylcholine (ACh) levels during non-rapid eye movement (NREM) sleep mediate stabilization of network-wide firing patterns, with temporal order of neurons' firing dependent on their mean firing rate during wake. In both reduced models and in vivo recordings from mouse hippocampus, we find that the relative order of firing among neurons during NREM sleep reflects their relative firing rates during prior wake. Our modeling results show that this remapping of wake-associated, firing frequency-based representations is based on NREM-associated changes in neuronal excitability mediated by ACh-gated potassium current. We also show that learning-dependent reordering of sequential firing during NREM sleep, together with spike timing-dependent plasticity (STDP), reconfigures neuronal firing rates across the network. This rescaling of firing rates has been reported in multiple brain circuits across periods of sleep. Our model and experimental data both suggest that this effect is amplified in neural circuits following learning. Together our data suggest that sleep may bias neural networks from firing rate-based towards phase-based information encoding to consolidate memories.

Theta-gamma coupling emerges from spatially heterogeneous cholinergic neuromodulation.

Theta and gamma rhythms and their cross-frequency coupling play critical roles in perception, attention, learning, and memory. Available data suggest that forebrain acetylcholine (ACh) signaling promotes theta-gamma coupling, although the mechanism has not been identified. Recent evidence suggests that cholinergic signaling is both temporally and spatially constrained, in contrast to the traditional notion of slow, spatially homogeneous, and diffuse neuromodulation. Here, we find that spatially constrained cholinergic stimulation can generate theta-modulated gamma rhythms. Using biophysically-based excitatory-inhibitory (E-I) neural network models, we simulate the effects of ACh on neural excitability by varying the conductance of a muscarinic receptor-regulated K+ current. In E-I networks with local excitatory connectivity and global inhibitory connectivity, we demonstrate that theta-gamma-coupled firing patterns emerge in ACh modulated network regions. Stable gamma-modulated firing arises within regions with high ACh signaling, while theta or mixed theta-gamma activity occurs at the peripheries of these regions. High gamma activity also alternates between different high-ACh regions, at theta frequency. Our results are the first to indicate a causal role for spatially heterogenous ACh signaling in the emergence of localized theta-gamma rhythmicity. Our findings also provide novel insights into mechanisms by which ACh signaling supports the brain region-specific attentional processing of sensory information.

Correction: Contrasting mechanisms for hidden hearing loss: Synaptopathy vs myelin defects.

[This corrects the article DOI: 10.1371/journal.pcbi.1008499.].

Contrasting mechanisms for hidden hearing loss: Synaptopathy vs myelin defects.

Hidden hearing loss (HHL) is an auditory neuropathy characterized by normal hearing thresholds but reduced amplitudes of the sound-evoked auditory nerve compound action potential (CAP). In animal models, HHL can be caused by moderate noise exposure or aging, which induces loss of inner hair cell (IHC) synapses. In contrast, recent evidence has shown that transient loss of cochlear Schwann cells also causes permanent auditory deficits in mice with similarities to HHL. Histological analysis of the cochlea after auditory nerve remyelination showed a permanent disruption of the myelination patterns at the heminode of type I spiral ganglion neuron (SGN) peripheral terminals, suggesting that this defect could be contributing to HHL. To shed light on the mechanisms of different HHL scenarios observed in animals and to test their impact on type I SGN activity, we constructed a reduced biophysical model for a population of SGN peripheral axons whose activity is driven by a well-accepted model of cochlear sound processing. We found that the amplitudes of simulated sound-evoked SGN CAPs are lower and have greater latencies when heminodes are disorganized, i.e. they occur at different distances from the hair cell rather than at the same distance as in the normal cochlea. These results confirm that disruption of heminode positions causes desynchronization of SGN spikes leading to a loss of temporal resolution and reduction of the sound-evoked SGN CAP. Another mechanism resulting in HHL is loss of IHC synapses, i.e., synaptopathy. For comparison, we simulated synaptopathy by removing high threshold IHC-SGN synapses and found that the amplitude of simulated sound-evoked SGN CAPs decreases while latencies remain unchanged, as has been observed in noise exposed animals. Thus, model results illuminate diverse disruptions caused by synaptopathy and demyelination on neural activity in auditory processing that contribute to HHL as observed in animal models and that can contribute to perceptual deficits induced by nerve damage in humans.

Dynamical Mechanism Underlying Scale-Free Network Reorganization in Low Acetylcholine States Corresponding to Slow Wave Sleep.

Sleep is indispensable for most animals' cognitive functions, and is hypothesized to be a major factor in memory consolidation. Although we do not fully understand the mechanisms of network reorganisation driving memory consolidation, available data suggests that sleep-associated neurochemical changes may be important for such processes. In particular, global acetylcholine levels change across the sleep/wake cycle, with high cholinergic tone during wake and REM sleep and low cholinergic tone during slow wave sleep. Furthermore, experimental perturbation of cholinergic tone has been shown to impact memory storage. Through in silico modeling of neuronal networks, we show how spiking dynamics change in highly heterogenous networks under varying levels of cholinergic tone, with neuronal networks under high cholinergic modulation firing asynchronously and at high frequencies, while those under low cholinergic modulation exhibit synchronous patterns of activity. We further examined the network's dynamics and its reorganization mediated via changing levels of acetylcholine within the context of different scale-free topologies, comparing network activity within the hub cells, a small group of neurons having high degree connectivity, and with the rest of the network. We show a dramatic, state-dependent change in information flow throughout the network, with highly active hub cells integrating information in a high-acetylcholine state, and transferring it to rest of the network in a low-acetylcholine state. This result is experimentally corroborated by frequency-dependent frequency changes observed in vivo experiments. Together, these findings provide insight into how new neurons are recruited into memory traces during sleep, a mechanism which may underlie system memory consolidation.

Phasic cholinergic signaling promotes emergence of local gamma rhythms in excitatory-inhibitory networks.

Recent experimental results have shown that the detection of cues in behavioral attention tasks relies on transient increases of acetylcholine (ACh) release in frontal cortex and cholinergically driven oscillatory activity in the gamma frequency band (Howe et al. Journal of Neuroscience, 2017, 37, 3215). The cue-induced gamma rhythmic activity requires stimulation of M1 muscarinic receptors. Using biophysical computational modeling, we show that a network of excitatory (E) and inhibitory (I) neurons that initially displays asynchronous firing can generate transient gamma oscillatory activity in response to simulated brief pulses of ACh. ACh effects are simulated as transient modulation of the conductance of an M-type K+ current which is blocked by activation of muscarinic receptors and has significant effects on neuronal excitability. The ACh-induced effects on the M current conductance, gKs , change network dynamics to promote the emergence of network gamma rhythmicity through a Pyramidal-Interneuronal Network Gamma mechanism. Depending on connectivity strengths between and among E and I cells, gamma activity decays with the simulated gKs transient modulation or is sustained in the network after the gKs transient has completely dissipated. We investigated the sensitivity of the emergent gamma activity to synaptic strengths, external noise and simulated levels of gKs modulation. To address recent experimental findings that cholinergic signaling is likely spatially focused and dynamic, we show that localized gKs modulation can induce transient changes of cellular excitability in local subnetworks, subsequently causing population-specific gamma oscillations. These results highlight dynamical mechanisms underlying localization of ACh-driven responses and suggest that spatially localized, cholinergically induced gamma may contribute to selectivity in the processing of competing external stimuli, as occurs in attentional tasks.

Network and cellular mechanisms underlying heterogeneous excitatory/inhibitory balanced states.

Recent work has explored spatiotemporal relationships between excitatory (E) and inhibitory (I) signaling within neural networks, and the effect of these relationships on network activity patterns. Data from these studies have indicated that excitation and inhibition are maintained at a similar level across long time periods and that excitatory and inhibitory currents may be tightly synchronized. Disruption of this balance-leading to an aberrant E/I ratio-is implicated in various brain pathologies. However, a thorough characterization of the relationship between E and I currents in experimental settings is largely impossible, due to their tight regulation at multiple cellular and network levels. Here, we use biophysical neural network models to investigate the emergence and properties of balanced states by heterogeneous mechanisms. Our results show that a network can homeostatically regulate the E/I ratio through interactions among multiple cellular and network factors, including average firing rates, synaptic weights and average neural depolarization levels in excitatory/inhibitory populations. Complex and competing interactions between firing rates and depolarization levels allow these factors to alternately dominate network dynamics in different synaptic weight regimes. This leads to the emergence of distinct mechanisms responsible for determining a balanced state and its dynamical correlate. Our analysis provides a comprehensive picture of how E/I ratio changes when manipulating specific network properties, and identifies the mechanisms regulating E/I balance. These results provide a framework to explain the diverse, and in some cases, contradictory experimental observations on the E/I state in different brain states and conditions.

Acetylcholine Mediates Dynamic Switching Between Information Coding Schemes in Neuronal Networks.

Rate coding and phase coding are the two major coding modes seen in the brain. For these two modes, network dynamics must either have a wide distribution of frequencies for rate coding, or a narrow one to achieve stability in phase dynamics for phase coding. Acetylcholine (ACh) is a potent regulator of neural excitability. Acting through the muscarinic receptor, ACh reduces the magnitude of the potassium M-current, a hyperpolarizing current that builds up as neurons fire. The M-current contributes to several excitability features of neurons, becoming a major player in facilitating the transition between Type 1 (integrator) and Type 2 (resonator) excitability. In this paper we argue that this transition enables a dynamic switch between rate coding and phase coding as levels of ACh release change. When a network is in a high ACh state variations in synaptic inputs will lead to a wider distribution of firing rates across the network and this distribution will reflect the network structure or pattern of external input to the network. When ACh is low, network frequencies become narrowly distributed and the structure of a network or pattern of external inputs will be represented through phase relationships between firing neurons. This work provides insights into how modulation of neuronal features influences network dynamics and information processing across brain states.

Synaptic Failure Differentially Affects Pattern Formation in Heterogenous Networks.

The communication of neurons is primarily maintained by synapses, which play a crucial role in the functioning of the nervous system. Therefore, synaptic failure may critically impair information processing in the brain and may underlie many neurodegenerative diseases. A number of studies have suggested that synaptic failure may preferentially target neurons with high connectivity (i.e., network hubs). As a result, the activity of these highly connected neurons can be significantly affected. It has been speculated that anesthetics regulate conscious state by affecting synaptic transmission at these network hubs and subsequently reducing overall coherence in the network activity. In addition, hubs in cortical networks are shown to be more vulnerable to amyloid deposition because of their higher activity within the network, causing decrease in coherence patterns and eventually Alzheimer's disease (AD). Here, we investigate how synaptic failure can affect spatio-temporal dynamics of scale free networks, having a power law scaling of number of connections per neuron - a relatively few neurons (hubs) with a lot of emanating or incoming connections and many cells with low connectivity. We studied two types of synaptic failure: activity-independent and targeted, activity-dependent synaptic failure. We defined scale-free network structures based on the dominating direction of the connections at the hub neurons: incoming and outgoing. We found that the two structures have significantly different dynamical properties. We show that synaptic failure may not only lead to the loss of coherence but unintuitively also can facilitate its emergence. We show that this is because activity-dependent synaptic failure homogenizes the activity levels in the network creating a dynamical substrate for the observed coherence increase. Obtained results may lead to better understanding of changes in large-scale pattern formation during progression of neuro-degenerative diseases targeting synaptic transmission.

How rhythms of the sleeping brain tune memory and synaptic plasticity.

Decades of neurobehavioral research has linked sleep-associated rhythms in various brain areas to improvements in cognitive performance. However, it remains unclear what synaptic changes might underlie sleep-dependent declarative memory consolidation and procedural task improvement, and why these same changes appear not to occur across a similar interval of wake. Here we describe recent research on how one specific feature of sleep-network rhythms characteristic of rapid eye movement and non-rapid eye movement-could drive synaptic strengthening or weakening in specific brain circuits. We provide an overview of how these rhythms could affect synaptic plasticity individually and in concert. We also present an overarching hypothesis for how all network rhythms occurring across the sleeping brain could aid in encoding new information in neural circuits.

Hippocampal Network Oscillations Rescue Memory Consolidation Deficits Caused by Sleep Loss.

Oscillations in the hippocampal network during sleep are proposed to play a role in memory storage by patterning neuronal ensemble activity. Here we show that following single-trial fear learning, sleep deprivation (which impairs memory consolidation) disrupts coherent firing rhythms in hippocampal area CA1. State-targeted optogenetic inhibition of CA1 parvalbumin-expressing (PV+) interneurons during postlearning NREM sleep, but not REM sleep or wake, disrupts contextual fear memory (CFM) consolidation in a manner similar to sleep deprivation. NREM-targeted inhibition disrupts CA1 network oscillations which predict successful memory storage. Rhythmic optogenetic activation of PV+ interneurons following learning generates CA1 oscillations with coherent principal neuron firing. This patterning of CA1 activity rescues CFM consolidation in sleep-deprived mice. Critically, behavioral and optogenetic manipulations that disrupt CFM also disrupt learning-induced stabilization of CA1 ensembles' communication patterns in the hours following learning. Conversely, manipulations that promote CFM also promote long-term stability of CA1 communication patterns. We conclude that sleep promotes memory consolidation by generating coherent rhythms of CA1 network activity, which provide consistent communication patterns within neuronal ensembles. Most importantly, we show that this rhythmic patterning of activity is sufficient to promote long-term memory storage in the absence of sleep.

Resonance with subthreshold oscillatory drive organizes activity and optimizes learning in neural networks.

Network oscillations across and within brain areas are critical for learning and performance of memory tasks. While a large amount of work has focused on the generation of neural oscillations, their effect on neuronal populations' spiking activity and information encoding is less known. Here, we use computational modeling to demonstrate that a shift in resonance responses can interact with oscillating input to ensure that networks of neurons properly encode new information represented in external inputs to the weights of recurrent synaptic connections. Using a neuronal network model, we find that due to an input current-dependent shift in their resonance response, individual neurons in a network will arrange their phases of firing to represent varying strengths of their respective inputs. As networks encode information, neurons fire more synchronously, and this effect limits the extent to which further "learning" (in the form of changes in synaptic strength) can occur. We also demonstrate that sequential patterns of neuronal firing can be accurately stored in the network; these sequences are later reproduced without external input (in the context of subthreshold oscillations) in both the forward and reverse directions (as has been observed following learning in vivo). To test whether a similar mechanism could act in vivo, we show that periodic stimulation of hippocampal neurons coordinates network activity and functional connectivity in a frequency-dependent manner. We conclude that resonance with subthreshold oscillations provides a plausible network-level mechanism to accurately encode and retrieve information without overstrengthening connections between neurons.

Functional network stability and average minimal distance - A framework to rapidly assess dynamics of functional network representations.

BACKGROUND: Recent advances in neurophysiological recording techniques have increased both the spatial and temporal resolution of data. New methodologies are required that can handle large data sets in an efficient manner as well as to make quantifiable, and realistic, predictions about the global modality of the brain from under-sampled recordings. NEW METHOD: To rectify both problems, we first propose an analytical modification to an existing functional connectivity algorithm, Average Minimal Distance (AMD), to rapidly capture functional network connectivity. We then complement this algorithm by introducing Functional Network Stability (FuNS), a metric that can be used to quickly assess the global network dynamic changes over time, without being constrained by the activities of a specific set of neurons. RESULTS: We systematically test the performance of AMD and FuNS (1) on artificial spiking data with different statistical characteristics, (2) from spiking data generated using a neural network model, and (3) using in vivo data recorded from mouse hippocampus during fear learning. Our results show that AMD and FuNS are able to monitor the change in network dynamics during memory consolidation. COMPARISON WITH OTHER METHODS: AMD outperforms traditional bootstrapping and cross-correlation (CC) methods in both significance and computation time. Simultaneously, FuNS provides a reliable way to establish a link between local structural network changes, global dynamics of network-wide representations activity, and behavior. CONCLUSIONS: The AMD-FuNS framework should be universally useful in linking long time-scale, global network dynamics and cognitive behavior.