Deep Brain Stimulation for Obsessive Compulsive Disorder: Evolution of Surgical Stimulation Target Parallels Changing Model of Dysfunctional Brain Circuits

Obsessive compulsive disorder (OCD) is a common, disabling psychiatric disease characterized by persistent, intrusive thoughts and ritualistic, repetitive behaviors. Deep brain stimulation (DBS) is thought to alleviate OCD symptoms by modulating underlying disturbances in normal cortico-striato-thalamo-cortical (CSTC) circuitry. Stimulation of the ventral portion of the anterior limb of the internal capsule (ALIC) and underlying ventral striatum (“ventral capsule/ventral striatum” or “VC/VS” target) received U.S. FDA approval in 2009 for patients with severe, treatment-refractory OCD. Over the decades, DBS surgical outcome studies have led to an evolution in the electrical stimulation target. In parallel, advancements in neuroimaging techniques have allowed investigators to better visualize and define CSTC circuits underlying the pathophysiology of OCD. A critical analysis of these new data suggests that the therapeutic mechanism of DBS for OCD likely involves neuromodulation of a widespread cortical/subcortical network, accessible by targeting fiber bundles in the ventral ALIC that connect broad network regions. Future studies will include advances in structural and functional imaging, analysis of physiological recordings, and utilization of next-generation DBS devices. These tools will enable patient-specific optimization of DBS therapy, which will hopefully further improve outcomes

A proteomic approach based on peptide affinity chromatography, 2-dimensional electrophoresis and mass spectrometry to identify multiprotein complexes interacting with membrane-bound receptors

There is accumulating evidence that membrane-bound receptors interact with many intracellular proteins. Multiprotein complexes associated with ionotropic receptors have been extensively characterized, but the identification of proteins interacting with G protein-coupled receptors (GPCRs) has so far only been achieved in a piecemeal fashion, focusing on one or two protein species. We describe a method based on peptide affinity chromatography, two-dimensional electrophoresis, mass spectrometry and immunoblotting to identify the components of multiprotein complexes interacting directly or indirectly with intracellular domains of GPCRs or, more generally, any other membrane-bound receptor. Using this global approach, we have characterized multiprotein complexes that bind to the carboxy-terminal tail of the 5-hydroxytryptamine type 2C receptor and are important for its subcellular localization in CNS cells (Bécamel et al., EMBO J., 21(10): 2332, 2002)

Automated entire thrombus density measurements for robust and comprehensive thrombus characterization in patients with acute ischemic stroke

Background and Purpose: In acute ischemic stroke (AIS) management, CT-based thrombus density has been associated with treatment success. However, currently used thrombus measurements are prone to inter-observer variability and oversimplify the heterogeneous thrombus composition. Our aim was first to introduce an automated method to assess the entire thrombus density and then to compare the measured entire thrombus density with respect to current standard manual measurements. Materials and Method: In 135 AIS patients, the density distribution of the entire thrombus was determined. Density distributions were described usingmedians, interquartile ranges (IQR), kurtosis, and skewedness. Differences between themedian of entire thrombusmeasurements and commonly applied manualmeasurements using 3 regions of interest were determined using linear regression. Results: Density distributions varied considerably with medians ranging from 20.0 to 62.8 HU and IQRs ranging from 9.3 to 55.8 HU. The average median of the thrombus density distributions (43.5 ± 10.2 HU) was lower than the manual assessment (49.6 ± 8.0 HU) (p<0.05). The difference between manual measurements and median density of entire thrombus decreased with increasing density (r = 0.64; p<0.05), revealing relatively higher manual measurements for low density thrombi such that manual density measurement tend overestimates the real thrombus density. Conclusions: Automatic measurements of the full thrombus expose a wide variety of thrombi density distribution, which is not grasped with currently used manual measurement. Furthermore, d

Two-year clinical follow-up of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN): Design and statistical analysis plan of the extended follow-up study

Background: MR CLEAN was the first randomized trial to demonstrate the short-term clinical effectiveness of endovascular treatment in patients with acute ischemic stroke caused by large vessel occlusion in the anterior circulation. Several other trials confirmed that endovascular treatment improves clinical outcome at three months. However, limited data are available on long-term clinical outcome. We aimed to estimate the effect of endovascular treatment on functional outcome at two-year follow-up in patients with acute ischemic stroke. Secondly, we aimed to assess the effect of endovascular treatment on major vascular events and mortality during two years of follow-up. Methods: MR CLEAN is a multicenter clinical trial with randomized treatment allocation, open-label treatment, and blinded endpoint evaluation. Patients included were 18 years or older with acute ischemic stroke caused by a proven anterior proximal artery occlusion who could be treated within six hours after stroke onset. The intervention contrast was endovascular treatment and usual care versus no endovascular treatment and usual care. The current study extended the follow-up duration from three months to two years. The primary outcome is the score on the modified Rankin scale at two years. Secondary outcomes include all-cause mortality and the occurrence of major vascular events within two years of follow-up. Discussion: The results of our study provide information on the long-term clinical effectiveness of endovascular treatment, which may have implications for individual treatment decisions and estimates of cost-effectiveness. Trial registration:NTR1804. Registered on 7 May 2009; ISRCTN10888758. Registered on 24 July 2012 (main MR CLEAN trial); NTR5073. Registered on 26 February 2015 (extended follow-up study)

IXPE and XMM-Newton observations of the Soft Gamma Repeater SGR 1806-20

Recent observations with the Imaging X-ray Polarimetry Explorer (IXPE) of two anomalous X-ray pulsars provided evidence that X-ray emission from magnetar sources is strongly polarized. Here we report on the joint IXPE and XMM-Newton observations of the soft {\gamma}-repeater SGR 1806-20. The spectral and timing properties of SGR 1806-20 derived from XMM-Newton data are in broad agreement with previous measurements; however, we found the source at an all-time-low persistent flux level. No significant polarization was measured apart from the 4-5 keV energy range, where a probable detection with PD=31.6\pm 10.5% and PA=-17.6\pm 15 deg was obtained. The resulting polarization signal, together with the upper limits we derive at lower and higher energies 2-4 and 5-8 keV, respectively) is compatible with a picture in which thermal radiation from the condensed star surface is reprocessed by resonant Compton scattering in the magnetosphere, similar to what proposed for the bright magnetar 4U 0142+61.Comment: 11 pages, 3 figures, accepted for publication in Ap

Antibiotic research and development: business as usual?

This article contends that poor economic incentives are an important reason for the lack of new drugs and explains how the DRIVE-AB intends to change the landscape by harnessing the expertise, motivation and diversity of its partner

X-ray pulsar GRO J1008−-57 as an orthogonal rotator

X-ray polarimetry is a unique way to probe geometrical configuration of highly-magnetized accreting neutron stars (X-ray pulsars). GRO J1008$-$57 is the first transient X-ray pulsar observed at two different flux levels by the Imaging X-ray Polarimetry Explorer (IXPE) during its outburst in November 2022. The polarization properties were found to be independent of the source luminosity, with the polarization degree varying between non-detection to about 15% over the pulse phase. Fitting the phase-resolved spectro-polarimetric data with the rotating vector model allowed us to estimate the pulsar inclination (130 deg, which is in good agreement with the orbital inclination), the position angle (75 deg) of the pulsar spin axis, and the magnetic obliquity (74 deg). This makes GRO J1008$-$57 the first confidently identified X-ray pulsar as a nearly orthogonal rotator. The results are discussed in the context of the neutron star atmosphere models and theories of pulsars' axis alignment.Comment: 11 pages, 7 figures, submitted to A&A. arXiv admin note: text overlap with arXiv:2209.0244

The Polarized Cosmic Hand: IXPE Observations of PSR B1509-58/MSH 15-52

We describe IXPE polarization observations of the Pulsar Wind Nebula (PWN) MSH15-52, the `Cosmic Hand'. We find X-ray polarization across the PWN, with B field vectors generally aligned with filamentary X-ray structures. High significance polarization is seen in arcs surrounding the pulsar and toward the end of the `jet', with polarization degree PD>70%, thus approaching the maximum allowed synchrotron value. In contrast, the base of the jet has lower polarization, indicating a complex magnetic field at significant angle to the jet axis. We also detect significant polarization from PSR B1509-58 itself. Although only the central pulse-phase bin of the pulse has high individual significance, flanking bins provide lower significance detections and, in conjunction with the X-ray image and radio polarization, can be used to constrain rotating vector model solutions for the pulsar geometry.Comment: To appear in the Astrophysical Journa

X-ray Polarization of the Eastern Lobe of SS 433

How astrophysical systems translate the kinetic energy of bulk motion into the acceleration of particles to very high energies is a pressing question. SS 433 is a microquasar that emits TeV gamma-rays indicating the presence of high-energy particles. A region of hard X-ray emission in the eastern lobe of SS 433 was recently identified as an acceleration site. We observed this region with the Imaging X-ray Polarimetry Explorer and measured a polarization degree in the range 38% to 77%. The high polarization degree indicates the magnetic field has a well ordered component if the X-rays are due to synchrotron emission. The polarization angle is in the range -12 to +10 degrees (east of north) which indicates that the magnetic field is parallel to the jet. Magnetic fields parallel to the bulk flow have also been found in supernova remnants and the jets of powerful radio galaxies. This may be caused by interaction of the flow with the ambient medium.Comment: 8 pages, accepted in the Astrophysical Journal Letter

X-Ray Polarimetry of the Dipping Accreting Neutron Star 4U 1624-49

We present the first X-ray polarimetric study of the dipping accreting neutron star 4U 1624$-$49 with the Imaging X-ray Polarimetry Explorer (IXPE). We report a detection of polarization in the non-dip time intervals with a confidence level of 99.99%. We find an average polarization degree (PD) of $3.1\pm0.7$% and a polarization angle of $81\pm6$ degrees east of north in the 2-8 keV band. We report an upper limit on the PD of 22% during the X-ray dips with 95% confidence. The PD increases with energy, reaching from $3.0\pm0.9$% in the 4-6 keV band to $6\pm2$% in the 6-8 keV band. This indicates the polarization likely arises from Comptonization. The high PD observed is unlikely to be produced by Comptonization in the boundary layer or spreading layer alone. It can be produced by the addition of an extended geometrically thin slab corona covering part of the accretion disk, as assumed in previous models of dippers, and/or a reflection component from the accretion disk