Sleep,Brain, and Cognition Special Feature: 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.

Spontaneous activity during quiescent periods and sleep is likely to be crucial for a multitude of cognitive functions. Functional connectivity studies from human neuroimaging and other brain monitoring modalities have identified several “resting-state networks” whose activity fluctuations are coordinated. One of them, the default mode network (DMN), increases its activity when the brain does not actively drive overt behavior and is involved in functions such as imagery, planning, self-reflection, and memory mechanism (1, 2). The dynamical interplay between hippocampus and the neocortex is another hallmark of the spontaneous activity during behavioral idleness. Hippocampal sharp waves/ripples (SWRs) (3), bursts of hippocampal activity, have attracted most attention as a conduit for this interplay, as they modulate neocortical activity (4–6). Interestingly, the DMN areas are among those most strongly activated at SWR times (7). SWRs are also linked to the bulk of memory replay in the hippocampus, which is the spontaneous repetition of neural activity patterns that were initially elicited during experience (8, 9). Replay has been observed also in many cortical areas (see, e.g., refs. 10–13), most strongly in correspondence with hippocampal SWRs.The interaction between the hippocampus and the neocortex figures prominently in most theories of explicit memory: The hippocampus is seen as rapidly forming rapid memories and “index codes” that summarize and point to activity patterns (14) that simultaneously (albeit more slowly) form in the neocortex and elsewhere in the brain. At memory retrieval, and during offline periods, those codes would propagate to the neocortex. Here, they would help seamlessly updating a large memory repository, as postulated by the complementary learning systems theory (15), or would create new, multiple memory traces [MMT theory (16)] with either similar content or semantic, gist-like representations (17).According to all of these theoretical accounts, however, cortico-hippocampal interplay likely involves the entirety of the neocortex. Yet, previous work has concentrated mostly on single neocortical areas, chosen among those with strongest anatomical links to the hippocampus. Functional magnetic resonance imaging (fMRI) (5) and voltage-sensitive imaging data (18) highlight the global character of neocortical activity modulations related to SWR, with a prominent role of the DMN (7), but how information propagates in neocortical networks is not known yet.During sleep cortical networks are capable of self-sustained high activity transients (UP states, periods of neuronal activation) delimited by silent periods (DOWN states, periods of neuronal silence) (19), generated by recurrent excitation across cortical neurons (20, 21). UP/DOWN state fluctuations have often been described as traveling waves (22–25), but little is known about the structure of each transient activation. Here, with voltage imaging in neocortex of mice combined with layer-resolved hippocampal local field potentials (LFPs), we characterize the probability distribution of transient sizes, showing that it approximates a power-law shape, signature of a near-critical state (in which long-range spatial and temporal correlation are maximized, facilitating global brain coordination), thought to maximize information transmission between far apart cortical sites (26, 27). Thus, these dynamics may be an effective support for the formation of neocortical memory traces.We further delineate the structure of activity transients in a data-driven manner and we find three functional networks centered respectively on the retrosplenial cortex and medial cortical bank of the cortex, on somatosensory cortex, and on lateral cortex. These networks closely match the results of a large anatomical projections dataset (28). Crucially, we show that they are differentially involved in hippocampal communication, with a “retrosplenial” network, overlapping with the standard DMN playing a prominent role.All the theoretical accounts mentioned above emphasize the hippocampal influence on the neocortex and a unidirectional flow from the hippocampus to neocortex, embodied in SWRs. Our data from voltage imaging and LFPs from hippocampal subfield CA1 suggest two refinements of this picture. First, the strongest correlate of cortical activity transients is the slow gamma rhythm (20 to 50 Hz), even outpacing SWRs. Slow gamma has been linked with the routing of information from hippocampal subfields CA3 to CA1. The CA3 subfield is rich in recurrent connections, features of an auto-associative memory (29–31). During sleep, increased slow gamma during SWR events correlates with greater replay (32). Furthermore, using pseudocausality analysis we show here that cortical transients in the DMN/retrosplenial network precede bouts of hippocampal slow gamma.Together, these data point toward a bidirectional interaction as a constituent of the overall architecture of cortico-hippocampal interactions, which provides a potential dynamical scenario. This picture opens up a theoretical view explaining the involvement of the DMN in memory and the two-way exchanges between hippocampus and neocortex, regions crucial for memory and cognition.     

Basal progesterone level as the main determinant of progesterone elevation on the day of hCG triggering in controlled ovarian stimulation cycles

Purpose

Modest increases of serum progesterone at human chorionic gonadotrophin (hCG) administration in controlled ovarian hyperstimulation (COH) cycles have been shown to have a negative impact on pregnancy outcomes. The aim of this study was to identify early predictors of progesterone elevation at hCG.

Design

Pregnancy outcome of 303 consecutive patients undergoing COH and fresh day-3 embryo transfer was analysed. Considering the non-linear relationship between progesterone at hCG triggering and pregnancy outcomes, partial area under the curve (pAUC) analysis was used to implement marker identification potential of receiver operating characteristic (ROC) curve analysis. Multivariate logistic analysis was then performed to identify predictors of progesterone rise.

Results

Pregnancy outcomes could be predicted by pAUC analysis (pAUC = 0.58, 95 % CI 0.51–0.66, p = 0.02) and a significant detrimental cut-off could be calculated (progesterone at hCG > 1.35 ng/ml). Total dose of rFSH administered, E₂ level at hCG but mostly basal progesterone level (OR = 12.21, 95 % CI 1.82–81.70) were predictors of progesterone rise above the cut-off.

Conclusion

Basal progesterone is shown to be the main prognostic factor for progesterone elevation. This observation should be taken into consideration in the clinical management of IVF/ICSI cycles to improve pregnancy outcomes.     

Molecular epidemiology of Mycobacterium tuberculosis clinical isolates in Southwest Ireland

Tuberculosis has had significant effects on Ireland over the past two centuries, causing persistently higher morbidity and mortality than in neighbouring countries until the last decade. This study describes the results of genotyping and drug susceptibility testing of 171 strains of Mycobacterium tuberculosis complex isolated between January 2004 and December 2006 in a region of Ireland centred on the city of Cork. Spoligotype comparisons were made with the SpolDB4 database and clustered 130 strains in 23 groups, forty-one strains showed unique Spoligotyping patterns. The commonest spoligotypes detected were ST0137 (X2) (16.9%), and ST0351 (15.8%) (‘U’ clade). The major spoligotype clades were X (26.2%), U (19.3%), T (15.2%), Beijing (5.9%), Haarlem (4.7%), LAM (4.1%), BOVIS (1.75%), with 12.9% unassigned strains. A 24-locus VNTR genotyping produced 15 clusters containing 49 isolates, with high discrimination index (HGDI > 0.99). A combination of Spoligotyping and VNTR reduced the number of clustered isolates to 47 in 15 clusters (27.5%). This study identified ST351 as common among Irish nationals, and found a low rate of drug resistance with little evidence of transmission of drug resistant strains. Strain clustering was significantly associated with age under 55 years and Irish nationality. Only strains of Euro-American lineage formed clusters. Molecular typing did not completely coincide with the results of contact investigations.     

An experimental investigation into the effect of periodic motion on proton dosimetry using polymer gel dosimeters and a programmable motion platform

Organ motion in proton therapy affects treatment dose distribution during both double-scattering (DS) and uniform-scanning (US) deliveries. We investigated the dosimetric impact of target motion using three-dimensional polymer gel dosimeters and a programmable motion platform. A simple one-beam treatment plan with 16 cm range and 6 cm modulation was generated from the treatment planning system (TPS) in both the DS and US modes. One gel dosimeter was irradiated with a stationary DS beam. Two other gel dosimeters were irradiated with the DS and US beams while they moved in the same sinusoidal motion profile using a programmable motion platform. The dose distribution of the stationary DS delivery agreed with the TPS plan. Dosimetric comparisons between DS motion delivery and the MATLAB-based motion model showed insignificant differences. Dose-volume histograms of a cylindrical target volume inside the gel dosimeters showed target coverage degradation caused by motion. A three-dimensional gamma index calculation (3% and 3 mm) confirmed different dosimetric impacts from DS and US with the same target motion. This polymer-gel-dosimeter-based study confirmed the dosimetric impact of intrafraction target motion and its interplay with temporal delivery of different energy layers in US proton treatments.     

Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia

Diamond-Blackfan anemia (DBA) is an inherited form of pure red cell aplasia that usually presents in infancy or early childhood and is associated with congenital malformations in ～30-50% of patients. DBA has been associated with mutations in nine ribosomal protein (RP) genes in about 53% of patients. We completed a large-scale screen of 79 RP genes by sequencing 16 RP genes (RPL3, RPL7, RPL8, RPL10, RPL14, RPL17, RPL19, RPL23A, RPL26, RPL27, RPL35, RPL36A, RPL39, RPS4X, RPS4Y1, and RPS21) in 96 DBA probands. We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities. This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits. We also found a deletion in RPL19 and missense mutations in RPL3 and RPL23A, which may be variants of unknown significance. Together with RPL5, RPL11, and RPS7, RPL26 is the fourth RP regulating p53 activity that is linked to DBA.     

Strong linkage disequilibrium for the frequent GJB2 35delG mutation in the Greek population

Approximately one in 1,000 children is affected by severe or profound hearing loss at birth or during early childhood (prelingual deafness). Up to 40% of congenital, autosomal recessive, severe to profound hearing impairment cases result from mutations in a single gene, GJB2, that encodes the connexin 26 protein. One specific mutation in this gene, 35delG, accounts for the majority of GJB2 mutations detected in Caucasian populations. Some previous studies have assumed that the high frequency of the 35delG mutation reflects the presence of a mutational hot spot, while other studies support the theory of a common founder. Greece is among the countries with the highest carrier frequency of the 35delG mutation (3.5%), and a recent study raised the hypothesis of the origin of this mutation in ancient Greece. We genotyped 60 Greek deafness patients homozygous for the 35delG mutation for six single nucleotide polymorphisms (SNPs) and two microsatellite markers inside or flanking the GJB2 gene. The allele distribution in the patients was compared to 60 Greek normal hearing controls. A strong linkage disequilibrium was found between the 35delG mutation and markers inside or flanking the GJB2 gene. Furthermore, we found a common haplotype with a previous study, suggesting a common founder for the 35delG mutation.