Mechanisms of deep brain stimulation for obsessive compulsive disorder: effects upon cells and circuits

Deep brain stimulation (DBS) has emerged as a safe, effective, and reversible treatment for a number of movement disorders. This has prompted investigation of its use for other applications including psychiatric disorders. In recent years, DBS has been introduced for the treatment of obsessive compulsive disorder (OCD), which is characterized by recurrent unwanted thoughts or ideas (obsessions) and repetitive behaviors or mental acts performed in order to relieve these obsessions (compulsions). Abnormal activity in cortico-striato-thalamo-cortical (CSTC) circuits including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), ventral striatum, and mediodorsal (MD) thalamus has been implicated in OCD. To this end a number of DBS targets including the anterior limb of the internal capsule (ALIC), ventral capsule/ventral striatum (VC/VS), ventral caudate nucleus, subthalamic nucleus (STN), and nucleus accumbens (NAc) have been investigated for the treatment of OCD. Despite its efficacy and widespread use in movement disorders, the mechanism of DBS is not fully understood, especially as it relates to psychiatric disorders. While initially thought to create a functional lesion akin to ablative procedures, it is increasingly clear that DBS may induce clinical benefit through activation of axonal fibers spanning the CSTC circuits, alteration of oscillatory activity within this network, and/or release of critical neurotransmitters. In this article we review how the use of DBS for OCD informs our understanding of both the mechanisms of DBS and the circuitry of OCD. We review the literature on DBS for OCD and discuss potential mechanisms of action at the neuronal level as well as the broader circuit level

Galaxy And Mass Assembly (GAMA) : The mechanisms for quiescent galaxy formation at z<1

© 2016 The Authors. One key problem in astrophysics is understanding how and why galaxies switch off their star formation, building the quiescent population that we observe in the local Universe. From the Galaxy And Mass Assembly and VIsible MultiObject Spectrograph Public Extragalactic Redshift surveys, we use spectroscopic indices to select quiescent and candidate transition galaxies.We identify potentially rapidly transitioning post-starburst (PSB) galaxies and slower transitioning green-valley galaxies. Over the last 8Gyr, the quiescent population has grown more slowly in number density at high masses (M * > 10 11 M ⊙ ) than at intermediate masses (M * > 10 10.6 M ⊙ ). There is evolution in both the PSB and green-valley stellar mass functions, consistent with higher mass galaxies quenching at earlier cosmic times.At intermediatemasses (M * > 10 10.6 M ⊙ ), we find a green-valley transition time-scale of 2.6 Gyr. Alternatively, at z ~ 0.7, the entire growth rate could be explained by fast-quenching PSB galaxies, with a visibility time-scale of 0.5 Gyr. At lower redshift, the number density of PSBs is so low that an unphysically short visibility window would be required for them to contribute significantly to the quiescent population growth. The importance of the fast-quenching route may rapidly diminish at z 10 11 M ⊙ ), there is tension between the large number of candidate transition galaxies compared to the slow growth of the quiescent population. This could be resolved if not all high-mass PSB and green-valley galaxies are transitioning from star forming to quiescent, for example if they rejuvenate out of the quiescent population following the accretion of gas and triggering of star formation, or if they fail to completely quench their star formation

The SAMI Galaxy Survey: : extraplanar gas, galactic winds, and their association with star formation history

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. ©: 2016 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society, the version of record is available on line at doi: 10.1093/mnras/stw017We investigate a sample of 40 local, main-sequence, edge-on disc galaxies using integral field spectroscopy with the Sydney-AAO Multi-object Integral field spectrograph (SAMI) Galaxy Survey to understand the link between properties of the extraplanar gas and their host galaxies. The kinematics properties of the extraplanar gas, including velocity asymmetries and increased dispersion, are used to differentiate galaxies hosting large-scale galactic winds from those dominated by the extended diffuse ionized gas. We find rather that a spectrum of diffuse gas-dominated to wind dominated galaxies exist. The wind-dominated galaxies span a wide range of star formation rates ($-1 \lesssim \log({\rm SFR/M_{\odot} yr^{-1}}) \lesssim 0.5$) across the whole stellar mass range of the sample ($8.5 \lesssim \log({\rm M_{*}/M_{\odot}}) \lesssim 11$). The wind galaxies also span a wide range in SFR surface densities ($10^{-3} \textrm{--} 10^{-1.5}\rm~M_{\odot} ~yr^{-1}~kpc^{-2}$) that is much lower than the canonical threshold of $\rm0.1~M_{\odot} ~yr^{-1}~kpc^{-2}$. The wind galaxies on average have higher SFR surface densities and higher $\rm H\delta_A$ values than those without strong wind signatures. The enhanced $\rm H\delta_A$ indicates that bursts of star formation in the recent past are necessary for driving large-scale galactic winds. We demonstrate with Sloan Digital Sky Survey data that galaxies with high SFR surface density have experienced bursts of star formation in the recent past. Our results imply that the galactic winds revealed in our study are indeed driven by bursts of star formation, and thus probing star formation in the time domain is crucial for finding and understanding galactic winds.Peer reviewe

In situ Biological Dose Mapping Estimates the Radiation Burden Delivered to ‘Spared’ Tissue between Synchrotron X-Ray Microbeam Radiotherapy Tracks

Microbeam radiation therapy (MRT) using high doses of synchrotron X-rays can destroy tumours in animal models whilst causing little damage to normal tissues. Determining the spatial distribution of radiation doses delivered during MRT at a microscopic scale is a major challenge. Film and semiconductor dosimetry as well as Monte Carlo methods struggle to provide accurate estimates of dose profiles and peak-to-valley dose ratios at the position of the targeted and traversed tissues whose biological responses determine treatment outcome. The purpose of this study was to utilise γ-H2AX immunostaining as a biodosimetric tool that enables in situ biological dose mapping within an irradiated tissue to provide direct biological evidence for the scale of the radiation burden to ‘spared’ tissue regions between MRT tracks. Γ-H2AX analysis allowed microbeams to be traced and DNA damage foci to be quantified in valleys between beams following MRT treatment of fibroblast cultures and murine skin where foci yields per unit dose were approximately five-fold lower than in fibroblast cultures. Foci levels in cells located in valleys were compared with calibration curves using known broadbeam synchrotron X-ray doses to generate spatial dose profiles and calculate peak-to-valley dose ratios of 30–40 for cell cultures and approximately 60 for murine skin, consistent with the range obtained with conventional dosimetry methods. This biological dose mapping approach could find several applications both in optimising MRT or other radiotherapeutic treatments and in estimating localised doses following accidental radiation exposure using skin punch biopsies

IL-13 is a driver of COVID-19 severity

Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here, we report that elevated IL-13 was associated with the need for mechanical ventilation in 2 independent patient cohorts. In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2–infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti–IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene, and accumulation of the hyaluronan (HA) polysaccharide was decreased in the lung. In patients with COVID-19, HA was increased in the lungs and plasma. Blockade of the HA receptor, CD44, reduced mortality in infected mice, supporting the importance of HA as a pathogenic mediator. Finally, HA was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and HA has important implications for therapy of COVID-19 and, potentially, other pulmonary diseases. IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of the disease, IL-13 neutralization reduced the disease and decreased lung HA deposition. Administration of IL-13–induced HA in the lung. Blockade of the HA receptor CD44 prevented mortality, highlighting a potentially novel mechanism for IL-13–mediated HA synthesis in pulmonary pathology

GAMA/G10-COSMOS/3D-HST: The 0<z<5 cosmic star-formation history, stellar- and dust-mass densities

We use the energy-balance code MAGPHYS to determine stellar and dust masses, and dust corrected star-formation rates for over 200,000 GAMA galaxies, 170,000 G10-COSMOS galaxies and 200,000 3D-HST galaxies. Our values agree well with previously reported measurements and constitute a representative and homogeneous dataset spanning a broad range in stellar mass (10^8---10^12 Msol), dust mass (10^6---10^9 Msol), and star-formation rates (0.01---100 Msol per yr), and over a broad redshift range (0.0 < z < 5.0). We combine these data to measure the cosmic star-formation history (CSFH), the stellar-mass density (SMD), and the dust-mass density (DMD) over a 12 Gyr timeline. The data mostly agree with previous estimates, where they exist, and provide a quasi-homogeneous dataset using consistent mass and star-formation estimators with consistent underlying assumptions over the full time range. As a consequence our formal errors are significantly reduced when compared to the historic literature. Integrating our cosmic star-formation history we precisely reproduce the stellar-mass density with an ISM replenishment factor of 0.50 +/- 0.07, consistent with our choice of Chabrier IMF plus some modest amount of stripped stellar mass. Exploring the cosmic dust density evolution, we find a gradual increase in dust density with lookback time. We build a simple phenomenological model from the CSFH to account for the dust mass evolution, and infer two key conclusions: (1) For every unit of stellar mass which is formed 0.0065---0.004 units of dust mass is also formed; (2) Over the history of the Universe approximately 90 to 95 per cent of all dust formed has been destroyed and/or ejected

Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1

Genome-wide analysis (GWA) is an effective strategy to discover extreme effects surpassing genome-wide significant levels in studying complex disorders; however, when sample size is limited, the true effects may fail to achieve genome-wide significance. In such case, there may be authentic results among the pools of nominal candidates, and an alternative approach is to consider nominal candidates but are replicable across different samples. Here, we found that mRNA expression of the choline dehydrogenase gene (CHDH) was uniformly upregulated in the brains of bipolar disorder (BPD) patients compared with healthy controls across different studies. Follow-up genetic analyses of CHDH variants in multiple independent clinical datasets (including 11,564 cases and 17,686 controls) identified a risk SNP rs9836592 showing consistent associations with BPD (P meta = 5.72 × 10(-4)), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 × 10(-16)). These converging results may identify a nominal but true BPD susceptibility gene CHDH. Further exploratory analysis revealed suggestive associations of rs9836592 with childhood intelligence (P = 0.044) and educational attainment (P = 0.0039), a 'proxy phenotype' of general cognitive abilities. Intriguingly, the CHDH gene is located at chromosome 3p21.1, a risk region implicated in previous BPD genome-wide association studies (GWAS), but CHDH is lying outside of the core GWAS linkage disequilibrium (LD) region, and our studied SNP rs9836592 is ∼1.2 Mb 3' downstream of the previous GWAS loci (e.g., rs2251219) with no LD between them; thus, the association observed here is unlikely a reflection of previous GWAS signals. In summary, our results imply that CHDH may play a previously unknown role in the etiology of BPD and also highlight the informative value of integrating gene expression and genetic code in advancing our understanding of its biological basis

Crystal structure of acetylcholine-binding protein from Bulinus truncatus reveals the conserved structural scaffold and sites of variation in nicotinic acetylcholine receptors

The crystal structure of acetylcholine-binding protein (AChBP) from the mollusk Lymnaea stagnalis is the established model for the ligand binding domains of the ligand-gated ion channel family, which includes nicotinic acetylcholine, 5-hydroxytryptamine (5-H