Ketamine decreases resting state functional connectivity between networks via the dorsal nexus: implications for major depression

Question: Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate modulating NMDA receptor antagonist ketamine [1, 2]. Targeting the glutamatergic system might thus provide a novel therapeutic strategy for antidepressant drug treatment [3]. Since glutamate is the most abundand and major excitatory neurotransmitter in the human brain, pathophysiological changes in glutamatergic signalling are likely to affect neurobehavioural plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder (MDD) [4]. Using resting state functional MRI (rsfMRI), the „dorsal nexus“ (DN) was recently identified as a bilateral dorsal medial prefrontal cortex (DMPFC) region showing dramatically increased depression-associated fMRI connectivity with large portions of the cognitive control network (CCN), the default mode network (DMN), and the affective network (AN) [5]. Hence, Sheline and colleagues [5] proposed that reducing increased connectivity of the DN might play a critical role in reducing depressive symptomatology and thus represent a potential therapeutic target for affective disorders. Since little is known about how ketamine affects large-scale neural network dynamics in the human brain, we aimed to test the hypothesis that ketamine as an antidepressant glutamatergic agent decreases resting state connectivties via the DN. Methods: Study design: 17 healthy subjects (mean age, 40.5 +/- 7.5 [SD]; 9 males) completed four resting state fMRI sessions in a double-blind, randomized, crossover study design (s. Fig 1). The baseline scan was followed by an intravenous infusion (45 mins) of either S-ketamine (0.25 mg/kg) or placebo (saline) outside the scanner. Since the antidepressant effect of ketamine is most prominent after one day [1], the followup scans were scheduled 24 hours after the ketamine or placebo infusion in order to assess the mid-term effects on neuronal network dynamics that might contribute to its antidepressant efficacy. To avoid a possible carry-over effect, the time lag between the two baseline measurements was set to at least 10 days. rsfMRI data acquisition and analysis: Measurements were performed on a Philips Achieva TX 3-T whole-body MR unit equipped with an 8-channel SENSE head coil. During each session a total of 200 functional images were collected in 10 minute runs (eyes closed) using the following acquisition parameters: TE = 35 ms, TR = 3000 ms (θ = 82°), FOV = 22 cm, acquisition matrix = 80 x 80 interpolated to 128 x 128, voxel size = 2.75 x 2.75 x 4 mm, 32 contiguous axial slices (placed along the anterior-posterior commissure plane), and sensitivity-encoded acceleration factor R = 2.0. A 3-dimensional T1-weighted anatomical scan was obtained for structural reference. Data were analyzed using the SPM8 (Wellcome Trust Center for Neuroimaging, London, England) based data processing assistant for resting state fMRI (DPARSF, by Yan Chao-Gan et al.) which includes a resting state fMRI data analysis toolkit (REST, by Song Xiao-Wei et al.). The postprocessing steps followed the standard protocol described by Yan and Zang (2010) [6]. Results: To test our hypothesis, we created a seed region of interest in the left and right DMPFC (10 mm sphere at ± 6 51 24) representing the DN. 24 h following ketamine administration, functional connectivity was exclusively reduced to the posterior cingulate cortex (PCC), to the subgenual anterior cingulate cortex (sgACC), and to anterior and mediodorsal parts of the thalamus (compared to placebo). The backprojection from a seed in the PCC confirmed these results and revealed an additional significant reduction of functional connectivity to the pregenual ACC (PACC) and medioprefrontal cortex (MPFC). For details, see Fig. 2 A, B and bar diagrams (functional connectivity change, paired t tests). Conclusion: While pharmacological effects of ketamine on task induced fMRI BOLD signals have been studied extensively, this is the first randomized, placebo-controlled, double-blind, crossover study demonstrating changes in resting state functional connectivity in response to ketamine administration in healthy subjects. Here, we report a significant decrease in functional connectivity of the sgACC (AN) and the PCC (DMN) via the DN 24 hours following ketamine administration, thus reflecting a neuronal pattern of normalization with regard to MDD where increased connectivities of the AN and DMN via the DN have been observed [5]. As critical hub of the AN, the sgACC plays an important role in mood regulation. Subgenual cortical activity was shown to be elevated in MDD and effective antidepressant treatment was associated with a reduction in sgACC activity [for review see ref. 7]. In addition, the observed reduction in functional connectivity between anterior (PACC/MPFC) and posterior parts of the DMN (PCC) may partially reverse the disrupted neurobehavioral homeostasis in MDD where a failure to normally down-regulate activity within the DMN during emotional stimulation was found [8], with increasing levels of DMN dominance being associated with higher levels of maladaptive, depressive rumination and lower levels of adaptive, reflective rumination [9]. Finally, reductions in cortico-thalamic connectivity may reflect functional alterations in thalamocortical loops via the prefrontal cortex. Based on the fact that the antidepressant effect of ketamine peaks one day after a single intravenous administration [1], we conclude that pharmacologically reducing the hyperconnectivity via the DN may play a critical role in reducing depressive symptomatology and in representing a systems level mechanism of treatment response for major depression

A Detailed Observational Analysis of V1324 Sco, the Most Gamma-Ray Luminous Classical Nova to Date

It has recently been discovered that some, if not all, classical novae emit GeV gamma rays during outburst, but the mechanisms involved in the production of the gamma rays are still not well understood. We present here a comprehensive multi-wavelength dataset---from radio to X-rays---for the most gamma-ray luminous classical nova to-date, V1324 Sco. Using this dataset, we show that V1324 Sco is a canonical dusty Fe-II type nova, with a maximum ejecta velocity of 2600 km s$^{-1}$ and an ejecta mass of few $\times 10^{-5}$ M$_{\odot}$. There is also evidence for complex shock interactions, including a double-peaked radio light curve which shows high brightness temperatures at early times. To explore why V1324~Sco was so gamma-ray luminous, we present a model of the nova ejecta featuring strong internal shocks, and find that higher gamma-ray luminosities result from higher ejecta velocities and/or mass-loss rates. Comparison of V1324~Sco with other gamma-ray detected novae does not show clear signatures of either, and we conclude that a larger sample of similarly well-observed novae is needed to understand the origin and variation of gamma rays in novae.Comment: 26 pages, 13 figure

Tamoxifen-Independent Recombination in the RIP-CreER Mouse

The inducible Cre-lox system is a valuable tool to study gene function in a spatial and time restricted fashion in mouse models. This strategy relies on the limited background activity of the modified Cre recombinase (CreER) in the absence of its inducer, the competitive estrogen receptor ligand, tamoxifen. The RIP-CreER mouse (Tg (Ins2-cre/Esr1) 1Dam) is among the few available β-cell specific CreER mouse lines and thus it has been often used to manipulate gene expression in the insulin-producing cells of the endocrine pancreas

Early spectral evolution of classical novae: consistent evidence for multiple distinct outflows

The physical mechanism driving mass ejection during a nova eruption is still poorly understood. Possibilities include ejection in a single ballistic event, a common envelope interaction, a continuous wind, or some combination of these processes. Here we present a study of 12 Galactic novae, for which we have pre-maximum high-resolution spectroscopy. All 12 novae show the same spectral evolution. Before optical peak, they show a slow P Cygni component. After peak a fast component quickly arises, while the slow absorption remains superimposed on top of it, implying the presence of at least two physically distinct flows. For novae with high-cadence monitoring, a third, intermediate-velocity component is also observed. These observations are consistent with a scenario where the slow component is associated with the initial ejection of the accreted material and the fast component with a radiation-driven wind from the white dwarf. When these flows interact, the slow flow is swept up by the fast flow, producing the intermediate component. These colliding flows may produce the gamma-ray emission observed in some novae. Our spectra also show that the transient heavy element absorption lines seen in some novae have the same velocity structure and evolution as the other lines in the spectrum, implying an association with the nova ejecta rather than a pre-existing circumbinary reservoir of gas or material ablated from the secondary. While this basic scenario appears to qualitatively reproduce multi-wavelength observations of classical novae, substantial theoretical and observational work is still needed to untangle the rich diversity of nova properties.Comment: 39 pages, 35 figures, submitted to Ap

Revisiting the classics: On the evolutionary origin of the "Fe II" and "He/N" spectral classes of novae

The optical spectra of novae are characterized by emission lines from the hydrogen Balmer series and either Fe II or He/N, leading to their traditional classification into two spectral classes: "Fe II" and "He/N". For decades, the origins of these spectral features were discussed in the literature in the contexts of different bodies of gas or changes in the opacity of the ejecta, particularly associated with studies by R. E. Williams and S. N. Shore. Here, we revisit these major studies with dedicated, modern data sets, covering the evolution of several novae from early rise to peak all the way to the nebular phase. Our data confirm previous suggestions in the literature that the "Fe II" and "He/N" spectral classes are phases in the spectroscopic evolution of novae driven primarily by changes in the opacity, ionization, and density of the ejecta, and most if not all novae go through at least three spectroscopic phases as their eruptions evolve: an early He/N (phase 1; observed during the early rise to visible peak and characterized by P Cygni lines of He I, N II, and N III), then an Fe II (phase 2; observed near visible peak and characterized by P Cygni lines of Fe II and O I), and then a later He/N (phase 3; observed during the decline and characterized by emission lines of He I. He II, N II, and N III), before entering the nebular phase. This spectral evolution seems to be ubiquitous across novae, regardless of their speed class; however the duration of each of these phase differs based on the speed class of the nova.Comment: 21 pages, 14 figures, 11 tables, Submitted to MNRA

Direct evidence for shock-powered optical emission in a nova

Classical novae are thermonuclear explosions that occur on the surfaces of white dwarf stars in interacting binary systems1. It has long been thought that the luminosity of classical novae is powered by continued nuclear burning on the surface of the white dwarf after the initial runaway2. However, recent observations of gigaelectronvolt γ-rays from classical novae have hinted that shocks internal to the nova ejecta may dominate the nova emission. Shocks have also been suggested to power the luminosity of events as diverse as stellar mergers3, supernovae4 and tidal disruption events5, but observational confirmation has been lacking. Here we report simultaneous space-based optical and γ-ray observations of the 2018 nova V906 Carinae (ASASSN-18fv), revealing a remarkable series of distinct correlated flares in both bands. The optical and γ-ray flares occur simultaneously, implying a common origin in shocks. During the flares, the nova luminosity doubles, implying that the bulk of the luminosity is shock powered. Furthermore, we detect concurrent but weak X-ray emission from deeply embedded shocks, confirming that the shock power does not appear in the X-ray band and supporting its emergence at longer wavelengths. Our data, spanning the spectrum from radio to γ-ray, provide direct evidence that shocks can power substantial luminosity in classical novae and other optical transients

Interactions between HIV-1 Reverse Transcriptase and the Downstream Template Strand in Stable Complexes with Primer-Template

Background: Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) forms stable ternary complexes in which RT is bound tightly at fixed positions on the primer-template (P/T). We have probed downstream interactions between RT and the template strand in the complex containing the incoming dNTP (+1 dNTPNRTNP/T complex) and in the complex containing the pyrophosphate analog, foscarnet (foscarnetNRTNP/T complex). Methods and Results: UV-induced cross-linking between RT and the DNA template strand was most efficient when a bromodeoxyuridine residue was placed in the +2 position (the first template position downstream from the incoming dNTP). Furthermore, formation of the +1 dNTPNRTNP/T complex on a biotin-containing template inhibited binding of streptavidin when biotin was in the +2 position on the template but not when the biotin was in the +3 position. Streptavidin pre-bound to a biotin residue in the template caused RT to stall two to three nucleotides upstream from the biotin residue. The downstream border of the complex formed by the stalled RT was mapped by digestion with exonuclease RecJF. UV-induced cross-linking of the complex formed by the pyrophosphate analog, foscarnet, with RT and P/T occurred preferentially with bromodeoxyuridine in the +1 position on the template in keeping with the location of RT one base upstream in the foscarnetNRTNP/T complex (i.e., in the pre-translocation position). Conclusions: For +1 dNTPNRTNP/T and foscarnetNRTNP/T stable complexes, tight interactions were observed between RT an

Clustering of Unhealthy Behaviors in the Aerobics Center Longitudinal Study

Background Clustering of unhealthy behaviors has been reported in previous studies; however the link with all-cause mortality and differences between those with and without chronic disease requires further investigation. Objectives To observe the clustering effects of unhealthy diet, fitness, smoking, and excessive alcohol consumption in adults with and without chronic disease and to assess all-cause mortality risk according to the clustering of unhealthy behaviors. Methods Participants were 13,621 adults (aged 20–84) from the Aerobics Center Longitudinal Study. Four health behaviors were observed (diet, fitness, smoking, and drinking). Baseline characteristics of the study population and bivariate relations between pairs of the health behaviors were evaluated separately for those with and without chronic disease using cross-tabulation and a chi-square test. The odds of partaking in unhealthy behaviors were also calculated. Latent class analysis (LCA) was used to assess clustering. Cox regression was used to assess the relationship between the behaviors and mortality. Results The four health behaviors were related to each other. LCA results suggested that two classes existed. Participants in class 1 had a higher probability of partaking in each of the four unhealthy behaviors than participants in class 2. No differences in health behavior clustering were found between participants with and without chronic disease. Mortality risk increased relative to the number of unhealthy behaviors participants engaged in. Conclusion Unhealthy behaviors cluster together irrespective of chronic disease status. Such findings suggest that multi-behavioral intervention strategies can be similar in those with and without chronic disease