Replay, the default mode network and the cascaded memory systems model.

The spontaneous replay of patterns of activity related to past experiences and memories is a striking feature of brain activity, as is the coherent activation of sets of brain areas - particularly those comprising the default mode network (DMN) - during rest. We propose that these two phenomena are strongly intertwined and that their potential functions overlap. In the 'cascaded memory systems model' that we outline here, we hypothesize that the DMN forms the backbone for the propagation of replay, mediating interactions between the hippocampus and the neocortex that enable the consolidation of new memories. The DMN may also independently ignite replay cascades, which support reactivation of older memories or high-level semantic representations. We suggest that transient cortical activations, inducing long-range correlations across the neocortex, are a key mechanism supporting a hierarchy of representations that progresses from simple percepts to semantic representations of causes and, finally, to whole episodes.

Hippocampal ripples coincide with "up-state" and spindles in retrosplenial cortex.

During NREM sleep, hippocampal sharp-wave ripple (SWR) events are thought to stabilize memory traces for long-term storage in downstream neocortical structures. Within the neocortex, a set of distributed networks organized around retrosplenial cortex (RS-network) interact preferentially with the hippocampus purportedly to consolidate those traces. Transient bouts of slow oscillations and sleep spindles in this RS-network are often observed around SWRs, suggesting that these two activities are related and that their interplay possibly contributes to memory consolidation. To investigate how SWRs interact with the RS-network and spindles, we combined cortical wide-field voltage imaging, Electrocorticography, and hippocampal LFP recordings in anesthetized and sleeping mice. Here, we show that, during SWR, "up-states" and spindles reliably co-occur in a cortical subnetwork centered around the retrosplenial cortex. Furthermore, retrosplenial transient activations and spindles predict slow gamma oscillations in CA1 during SWRs. Together, our results suggest that retrosplenial-hippocampal interaction may be a critical pathway of information exchange between the cortex and hippocampus.

Hippocampal gamma and sharp wave/ripples mediate bidirectional interactions with cortical networks during sleep.

Hippocampus-neocortex interactions during sleep are critical for memory processes: Hippocampally initiated replay contributes to memory consolidation in the neocortex and hippocampal sharp wave/ripples modulate cortical activity. Yet, the spatial and temporal patterns of this interaction are unknown. With voltage imaging, electrocorticography, and laminarly resolved hippocampal potentials, we characterized cortico-hippocampal signaling during anesthesia and nonrapid eye movement sleep. We observed neocortical activation transients, with statistics suggesting a quasi-critical regime, may be helpful for communication across remote brain areas. From activity transients, we identified, in a data-driven fashion, three functional networks. A network overlapping with the default mode network and centered on retrosplenial cortex was the most associated with hippocampal activity. Hippocampal slow gamma rhythms were strongly associated to neocortical transients, even more than ripples. In fact, neocortical activity predicted hippocampal slow gamma and followed ripples, suggesting that consolidation processes rely on bidirectional signaling between hippocampus and neocortex.

SpikeShip: A method for fast, unsupervised discovery of high-dimensional neural spiking patterns.

Neural coding and memory formation depend on temporal spiking sequences that span high-dimensional neural ensembles. The unsupervised discovery and characterization of these spiking sequences requires a suitable dissimilarity measure to spiking patterns, which can then be used for clustering and decoding. Here, we present a new dissimilarity measure based on optimal transport theory called SpikeShip, which compares multi-neuron spiking patterns based on all the relative spike-timing relationships among neurons. SpikeShip computes the optimal transport cost to make all the relative spike-timing relationships (across neurons) identical between two spiking patterns. We show that this transport cost can be decomposed into a temporal rigid translation term, which captures global latency shifts, and a vector of neuron-specific transport flows, which reflect inter-neuronal spike timing differences. SpikeShip can be effectively computed for high-dimensional neuronal ensembles, has a low (linear) computational cost that has the same order as the spike count, and is sensitive to higher-order correlations. Furthermore, SpikeShip is binless, can handle any form of spike time distributions, is not affected by firing rate fluctuations, can detect patterns with a low signal-to-noise ratio, and can be effectively combined with a sliding window approach. We compare the advantages and differences between SpikeShip and other measures like SPIKE and Victor-Purpura distance. We applied SpikeShip to large-scale Neuropixel recordings during spontaneous activity and visual encoding. We show that high-dimensional spiking sequences detected via SpikeShip reliably distinguish between different natural images and different behavioral states. These spiking sequences carried complementary information to conventional firing rate codes. SpikeShip opens new avenues for studying neural coding and memory consolidation by rapid and unsupervised detection of temporal spiking patterns in high-dimensional neural ensembles.

The object space task shows cumulative memory expression in both mice and rats.

Declarative memory encompasses representations of specific events as well as knowledge extracted by accumulation over multiple episodes. To investigate how these different sorts of memories are created, we developed a new behavioral task in rodents. The task consists of 3 distinct conditions (stable, overlapping, and random). Rodents are exposed to multiple sample trials, in which they explore objects in specific spatial arrangements, with object identity changing from trial to trial. In the stable condition, the locations are constant during all sample trials even though the objects themselves change; in the test trial, 1 object's location is changed. In the random condition, object locations are presented in the sample phase without a specific spatial pattern. In the overlapping condition, 1 location is shared (overlapping) between all trials, while the other location changes during sample trials. We show that in the overlapping condition, instead of only remembering the last sample trial, rodents form a cumulative memory of the sample trials. Here, we could show that both mice and rats can accumulate information across multiple trials and express a long-term abstracted memory.

Combining Cortical Voltage Imaging and Hippocampal Electrophysiology for Investigating Global, Multi-Timescale Activity Interactions in the Brain.

A new generation of optogenetic tools for analyzing neural activity has been contributing to the elucidation of classical open questions in neuroscience. Specifically, voltage imaging technologies using enhanced genetically encoded voltage indicators have been increasingly used to observe the dynamics of large circuits at the mesoscale. Here, we describe how to combine cortical wide-field voltage imaging with hippocampal electrophysiology in awake, behaving mice. Furthermore, we highlight how this method can be useful for different possible investigations, using the characterization of hippocampal-neocortical interactions as a case study.

Hepatobiliary Disease Resection in Patients with Advanced Epithelial Ovarian Cancer: Prognostic Role and Optimal Cytoreduction.

OBJECTIVE: The purpose of this study was to evaluate the feasibility and safety in terms of prognostic significance and perioperative morbidity and mortality of cytoreduction in patients affected by advance ovarian cancer and hepato-biliary metastasis. METHODS: Patients with a least one hepatobiliary metastasis who have undergone surgical treatment with curative intent of were considered for the study. Perioperative complications were evaluated and graded with Accordion severity Classification. Five-year PFS and OS were estimated using the Kaplan-Meier curve. RESULTS: Sixty-seven (20.9%) patients had at least one metastasis to the liver, biliary tract, or porta hepatis. Forty-four (65.7%) and 23 (34.3%) patients underwent respectively high and intermediate complexity surgery according. Complete cytoreduction was achieved in 48 (71.6%) patients with hepato-biliary disease. In two patients (2.9%) severe complications related to hepatobiliary surgery were reported. The median PFS for the patients with hepato-biliary involvement (RT = 0 vs. RT > 0) was 19 months [95% confidence interval (CI) 16.2-21.8] and 8 months (95% CI 6.1-9.9). The median OS for the patients with hepato-biliary involvement (RT = 0 vs. RT > 0) 45 months (95% CI 21.2-68.8 months) and 23 months (95% CI 13.9-32.03). CONCLUSIONS: Hepatobiliary involvement is often associated with high tumor load and could require high complex multivisceral surgery. In selected patients complete cytoreduction could offer survival benefits. Morbidity related to hepatobiliary procedures is acceptable. Careful evaluation of patients and multidisciplinary approach in referral centers is mandatory.

Impact of joint management of a COVID-19 mother and her newborn on the virus transmission: a case report.

BACKGROUND: Since last year, COVID-19, the disease caused by the novel Sars-Cov-2 virus, has been globally spread to all the world. COVID-19 infection among pregnant women has been described. However, transplacental transmission of Sars-Cov-2 virus from infected mother to the newborn is not yet established. The appropriate management of infants born to mothers with confirmed or suspected COVID-19 and the start of early breastfeeding are being debated. CASE PRESENTATION: We report a case of the joint management of a healthy neonate with his mother tested positive for Covid-19 before the delivery and throughout neonatal follow-up. The infection transmission from the mother to her baby is not described, even after a long period of contact between them and breastfeeding. CONCLUSION: It may consider an appropriate practice to keep mother and her newborn infant together in order to facilitate their contact and to encourage breastfeeding, although integration with infection prevention measures is needed.

The Role of 2D/3D Ultrasound to Assess the Response to Neoadjuvant Chemotherapy in Locally Advanced Cervical Cancer.

INTRODUCTION: Different imaging techniques were introduced to improve preoperative clinical staging of locally advanced cervical cancer (LACC) with transvaginal ultrasound (TV-US) or transrectal ultrasound (TR-US) representing a promising staging technique in the evaluation of the local extension of the disease for invasive tumors. The aim of this study was to evaluate the response to neoadjuvant chemotherapy (NACT) in LACC by 2D/3D ultrasound examination. MATERIALS AND METHODS: We prospectively enrolled patients affected by histologically and clinically confirmed LACC. All patients were scheduled for 3 cycles of platinum-based NACT followed by radical surgery. The ultrasound examination was performed at every cycle and within 10 days before surgery. The parameters evaluated were: the volume (automatically computed by the VOCAL software) and the mass vascularization. RESULTS: From March 2010 to March 2019, 157 women were recruited. Among these patients, 12 of them were excluded: 6 for the presence of distant metastases, 4 for rare histology, and 2 for severe comorbidities not allowing the protocol treatment. Seventeen patients after NACT were excluded because they were not amenable to radical surgery. Thus, 128 were considered for the final analysis of whom 106 (83%) were considered responders to NACT by histology. The sensibility and specificity of ultrasound with regard to the response to chemotherapy compared to histological specimen were 94 and 82%, respectively, with an accuracy of 92%. The positive predictive value and negative predictive value were 96 and 75%, respectively. Finally, we found that nonetheless there was a trend towards a continuous response to chemotherapy among patients who were considered responders to NACT at pathological examination; the major volume and vascularization index (VI) reduction were observed during the first 2 cycles (74, 71% and 47, 63%, respectively). On the contrary, non-responders showed an initial reduction of the VI (4.86 consisting of 33%, 95% CI 0.79-8.92, p = 0.013), but no significant modification in tumour volume along NACT. CONCLUSION: 2D/3D ultrasound is useful in assessing early response to NACT in patients with LACC.

The Yin and Yang of Memory Consolidation: Hippocampal and Neocortical.

While hippocampal and cortical mechanisms of memory consolidation have long been studied, their interaction is poorly understood. We sought to investigate potential interactions with respect to trace dominance, strengthening, and interference associated with postencoding novelty or sleep. A learning procedure was scheduled in a watermaze that placed the impact of novelty and sleep in opposition. Distinct behavioural manipulations-context preexposure or interference during memory retrieval-differentially affected trace dominance and trace survival, respectively. Analysis of immediate early gene expression revealed parallel up-regulation in the hippocampus and cortex, sustained in the hippocampus in association with novelty but in the cortex in association with sleep. These findings shed light on dynamically interacting mechanisms mediating the stabilization of hippocampal and neocortical memory traces. Hippocampal memory traces followed by novelty were more dominant by default but liable to interference, whereas sleep engaged a lasting stabilization of cortical traces and consequent trace dominance after preexposure.

Unsupervised clustering of temporal patterns in high-dimensional neuronal ensembles using a novel dissimilarity measure.

Temporally ordered multi-neuron patterns likely encode information in the brain. We introduce an unsupervised method, SPOTDisClust (Spike Pattern Optimal Transport Dissimilarity Clustering), for their detection from high-dimensional neural ensembles. SPOTDisClust measures similarity between two ensemble spike patterns by determining the minimum transport cost of transforming their corresponding normalized cross-correlation matrices into each other (SPOTDis). Then, it performs density-based clustering based on the resulting inter-pattern dissimilarity matrix. SPOTDisClust does not require binning and can detect complex patterns (beyond sequential activation) even when high levels of out-of-pattern "noise" spiking are present. Our method handles efficiently the additional information from increasingly large neuronal ensembles and can detect a number of patterns that far exceeds the number of recorded neurons. In an application to neural ensemble data from macaque monkey V1 cortex, SPOTDisClust can identify different moving stimulus directions on the sole basis of temporal spiking patterns.

Abnormal hippocampal theta and gamma hypersynchrony produces network and spike timing disturbances in the Fmr1-KO mouse model of Fragile X syndrome.

Neuronal networks can synchronize their activity through excitatory and inhibitory connections, which is conducive to synaptic plasticity. This synchronization is reflected in rhythmic fluctuations of the extracellular field. In the hippocampus, theta and gamma band LFP oscillations are a hallmark of the processing of spatial information and memory. Fragile X syndrome (FXS) is an intellectual disability and the most common genetic cause of autism spectrum disorder (Belmonte and Bourgeron, 2006). Here, we investigated how neuronal network synchronization in the mouse hippocampus is compromised by the Fmr1 mutation that causes FXS (Santos et al., 2014), relating recently observed single-cell level impairments (Arbab et al., 2017) to neuronal network aberrations. We implanted tetrodes in hippocampus of freely moving Fmr1-KO and littermate wildtype (WT) mice (Mientjes et al., 2006), to record spike trains from multiple, isolated neurons as well as LFPs in a spatial exploration paradigm. Compared to wild type mice, Fmr1-KO mice displayed greater power of hippocampal theta oscillations, and higher coherence in the slow gamma band. Additionally, spike trains of Fmr1-KO interneurons show decreased spike-count correlations and they are hypersynchronized with theta and slow gamma oscillations. The hypersynchronization of Fmr1-KO oscillations and spike timing reflects functional deficits in local networks. This network hypersynchronization pathologically decreases the heterogeneity of spike-LFP phase coupling, compromising information processing within the hippocampal circuit. These findings may reflect a pathophysiological mechanism explaining cognitive impairments in FXS and autism, in which there is anomalous processing of social and environmental cues and associated deficits in memory and cognition.

Lifestyle and fertility: the influence of stress and quality of life on female fertility.

There is growing evidence that lifestyle choices account for the overall quality of health and life (QoL) reflecting many potential lifestyle risks widely associated with alterations of the reproductive function up to the infertility. This review aims to summarize in a critical fashion the current knowledge about the potential effects of stress and QoL on female reproductive function. A specific literature search up to August 2017 was performed in IBSS, SocINDEX, Institute for Scientific Information, PubMed, Web of Science and Google Scholar. Current review highlights a close relationship in women between stress, QoL and reproductive function, that this association is more likely reported in infertile rather than fertile women, and that a vicious circle makes them to have supported each other. However, a precise cause-effect relationship is still difficult to demonstrate due to conflicting results and the lack of objective measures/instruments of evaluation.

Obstetric and perinatal outcomes in subfertile patients who conceived following low technology interventions for fertility enhancement: a comprehensive review.

PURPOSE: Low technology interventions for fertility enhancement (LTIFE) are strategies that avoid retrieval, handling, and manipulation of female gametes. The definition of LTIFE is yet to be widely accepted and clarified, but they are commonly used in milder cases of infertility and subfertility. Based on these considerations, the aim of the present study was comprehensively to review and investigate the obstetric and perinatal outcomes in subfertile patients who underwent LTIFE. METHODS: A literature search up to May 2017 was performed in IBSS, SocINDEX, Institute for Scientific Information, PubMed, Web of Science, and Google Scholar. An evidence-based hierarchy was used according to The Oxford Centre for Evidence-Based Medicine to determine which articles to include and analyze, and to provide a level of evidence of each association between intervention and outcome. RESULTS: This analysis identified preliminary and low-grade evidence on the influence of LTIFE on obstetric and perinatal outcomes in subfertile women. CONCLUSIONS: LTIFE women should deserve major consideration from Clinicians/Researchers of Reproductive Medicine, because these treatments could be potentially responsible for mothers' and babies' complications. So far, the lack of well-designed and unbiased studies makes further conclusions difficult to be drawn.

Effects of Arc/Arg3.1 gene deletion on rhythmic synchronization of hippocampal CA1 neurons during locomotor activity and sleep.

The activity-regulated cytoskeletal-associated protein/activity regulated gene (Arc/Arg3.1) is crucial for long-term synaptic plasticity and memory formation. However, the neurophysiological substrates of memory deficits occurring in the absence of Arc/Arg3.1 are unknown. We compared hippocampal CA1 single-unit and local field potential (LFP) activity in Arc/Arg3.1 knockout and wild-type mice during track running and flanking sleep periods. Locomotor activity, basic firing and spatial coding properties of CA1 cells in knockout mice were not different from wild-type mice. During active behavior, however, knockout animals showed a significantly shifted balance in LFP power, with a relative loss in high-frequency (beta-2 and gamma) bands compared to low-frequency bands. Moreover, during track-running, knockout mice showed a decrease in phase locking of spiking activity to LFP oscillations in theta, beta and gamma bands. Sleep architecture in knockout mice was not grossly abnormal. Sharp-wave ripples, which have been associated with memory consolidation and replay, showed only minor differences in dynamics and amplitude. Altogether, these findings suggest that Arc/Arg3.1 effects on memory formation are not only manifested at the level of molecular pathways regulating synaptic plasticity, but also at the systems level. The disrupted power balance in theta, beta and gamma rhythmicity and concomitant loss of spike-field phase locking may affect memory encoding during initial storage and memory consolidation stages.

Single-trial properties of place cells in control and CA1 NMDA receptor subunit 1-KO mice.

The NMDA receptor plays a key role in synaptic plasticity and its disruption leads to impaired spatial representation in the CA1 area of the hippocampus, with place cells exhibiting larger place fields (McHugh et al., 1996). Place fields are defined by the spatial and nonspatial inputs of a given place and context, by intrinsic network processes, such as phase precession, but also by the matching of these inputs to a pre-existing spatial representation. Larger place fields may be a consequence of spatially widened firing upon a single crossing of a place field, or of increased variability in place field positions across traversals. We addressed this question by monitoring CA1 place cell activity, with tetrodes, in control and KO mice lacking the NMDA receptor in this region. In individual crossings of the field, we found no difference between genotypes in place field size; the larger, overall place field size turns out to be a consequence of jitter across trials. We suggest that this jitter reflects a deficit in the matching of current spatial inputs to the stored spatial representation of the track. This is supported by the finding that deficits in place field size and spatial information are rescued by extensive exposure of the mouse to the track, which may echo an increased influence of memory retrieval processes in CA3 on firing in CA1.

How to detect the Granger-causal flow direction in the presence of additive noise?

Granger-causality metrics have become increasingly popular tools to identify directed interactions between brain areas. However, it is known that additive noise can strongly affect Granger-causality metrics, which can lead to spurious conclusions about neuronal interactions. To solve this problem, previous studies have proposed the detection of Granger-causal directionality, i.e. the dominant Granger-causal flow, using either the slope of the coherency (Phase Slope Index; PSI), or by comparing Granger-causality values between original and time-reversed signals (reversed Granger testing). We show that for ensembles of vector autoregressive (VAR) models encompassing bidirectionally coupled sources, these alternative methods do not correctly measure Granger-causal directionality for a substantial fraction of VAR models, even in the absence of noise. We then demonstrate that uncorrelated noise has fundamentally different effects on directed connectivity metrics than linearly mixed noise, where the latter may result as a consequence of electric volume conduction. Uncorrelated noise only weakly affects the detection of Granger-causal directionality, whereas linearly mixed noise causes a large fraction of false positives for standard Granger-causality metrics and PSI, but not for reversed Granger testing. We further show that we can reliably identify cases where linearly mixed noise causes a large fraction of false positives by examining the magnitude of the instantaneous influence coefficient in a structural VAR model. By rejecting cases with strong instantaneous influence, we obtain an improved detection of Granger-causal flow between neuronal sources in the presence of additive noise. These techniques are applicable to real data, which we demonstrate using actual area V1 and area V4 LFP data, recorded from the awake monkey performing a visual attention task.

How the amygdala affects emotional memory by altering brain network properties.

The amygdala has long been known to play a key role in supporting memory for emotionally arousing experiences. For example, classical fear conditioning depends on neural plasticity within this anterior medial temporal lobe region. Beneficial effects of emotional arousal on memory, however, are not restricted to simple associative learning. Our recollection of emotional experiences often includes rich representations of, e.g., spatiotemporal context, visceral states, and stimulus-response associations. Critically, such memory features are known to bear heavily on regions elsewhere in the brain. These observations led to the modulation account of amygdala function, which postulates that amygdala activation enhances memory consolidation by facilitating neural plasticity and information storage processes in its target regions. Rodent work in past decades has identified the most important brain regions and neurochemical processes involved in these modulatory actions, and neuropsychological and neuroimaging work in humans has produced a large body of convergent data. Importantly, recent methodological developments make it increasingly realistic to monitor neural interactions underlying such modulatory effects as they unfold. For instance, functional connectivity network modeling in humans has demonstrated how information exchanges between the amygdala and specific target regions occur within the context of large-scale neural network interactions. Furthermore, electrophysiological and optogenetic techniques in rodents are beginning to make it possible to quantify and even manipulate such interactions with millisecond precision. In this paper we will discuss that these developments will likely lead to an updated view of the amygdala as a critical nexus within large-scale networks supporting different aspects of memory processing for emotionally arousing experiences.

Inhibition recruitment in prefrontal cortex during sleep spindles and gating of hippocampal inputs.

During light slow-wave sleep, the thalamo-cortical network oscillates in waxing-and-waning patterns at about 7 to 14 Hz and lasting for 500 ms to 3 s, called spindles, with the thalamus rhythmically sending strong excitatory volleys to the cortex. Concurrently, the hippocampal activity is characterized by transient and strong excitatory events, Sharp-Waves-Ripples (SPWRs), directly affecting neocortical activity--in particular the medial prefrontal cortex (mPFC)--which receives monosynaptic fibers from the ventral hippocampus and subiculum. Both spindles and SPWRs have been shown to be strongly involved in memory consolidation. However, the dynamics of the cortical network during natural sleep spindles and how prefrontal circuits simultaneously process hippocampal and thalamo-cortical activity remain largely undetermined. Using multisite neuronal recordings in rat mPFC, we show that during sleep spindles, oscillatory responses of cortical cells are different for different cell types and cortical layers. Superficial neurons are more phase-locked and tonically recruited during spindle episodes. Moreover, in a given layer, interneurons were always more modulated than pyramidal cells, both in firing rate and phase, suggesting that the dynamics are dominated by inhibition. In the deep layers, where most of the hippocampal fibers make contacts, pyramidal cells respond phasically to SPWRs, but not during spindles. Similar observations were obtained when analyzing γ-oscillation modulation in the mPFC. These results demonstrate that during sleep spindles, the cortex is functionnaly "deafferented" from its hippocampal inputs, based on processes of cortical origin, and presumably mediated by the strong recruitment of inhibitory interneurons. The interplay between hippocampal and thalamic inputs may underlie a global mechanism involved in the consolidation of recently formed memory traces.

Placentation and complications of ART pregnancy. An update on the different possible etiopathogenic mechanisms involved in the development of obstetric complications.

INTRODUCTION: Infertile couples' percentage is increasing all over the world, especially in Italy, with high number of children born in our country through assisted reproductive techniques (ART). However, pregnancies obtained by ART have increased potential obstetrical risks which could be caused by fetus-placenta unit development, most of all due to placentation's evolution. These can be reassumed into miscarriage, chromosomal abnormalities, preterm delivery, multiple pregnancy, IUGR, placenta previa, abruptio placentae, preeclampsia and hypertensive disorders, postpartum hemorrhage. METHODS: The aim of this article is to evaluate hypothetic mechanism involved in placentation process and in the etiopathology of ART pregnancies disorders, giving an updating overview of different etiopathogenetic pathways and features. On this scenario, we create an updated review about the etiopathogenesis of abnormal placentation in ART pregnancies. RESULTS: Several features and different etiopathogenetic characteristic might impact differently such as advanced maternal age, poor ovarian reserve, oocyte quality and causes of subfertility themselves, and the ART techniques itself, as hormonal medical treatments and laboratory techniques such as gamete and embryo laboratory culture, cryopreservation versus fresh ET, number of embryos transferred. CONCLUSION: To further explore the molecular mechanisms behind placentation in ART pregnancies, further studies are necessary to gain a better understanding of the various aspects involved, particularly those which are not fully comprehended. This could prove beneficial to clinicians in both ART care and obstetric care, as it could help to stratify obstetrical risk and decrease complications in women undergoing ART, as well as perinatal disorders in their children. Correct placentation is essential for a successful pregnancy for both mother and baby.