Pilot Testing Behavior Therapy for Chronic Tic Disorders in Neurology and Developmental Pediatrics Clinics

Comprehensive Behavioral Intervention for Tics (CBIT) is an efficacious treatment with limited regional availability. As neurology and pediatric clinics are often the first point of therapeutic contact for individuals with tics, the present study assessed preliminary treatment response, acceptability, and feasibility of an abbreviated version, modified for child neurology and developmental pediatrics clinics. Fourteen youth (9-17) with Tourette disorder across 2 child neurology clinics and one developmental pediatrics clinic participated in a small case series. Clinician-rated tic severity (Yale Global Tic Severity Scale) decreased from pre- to posttreatment, z = –2.0, P \u3c .05, r = –.48, as did tic-related impairment, z = –2.4, P \u3c .05, r = –.57. Five of the 9 completers (56%) were classified as treatment responders. Satisfaction ratings were high, and therapeutic alliance ratings were moderately high. Results provide guidance for refinement of this modified CBIT protocol

A 3D-printed high power nuclear spin polarizer

[Image: see text] Three-dimensional printing with high-temperature plastic is used to enable spin exchange optical pumping (SEOP) and hyperpolarization of xenon-129 gas. The use of 3D printed structures increases the simplicity of integration of the following key components with a variable temperature SEOP probe: (i) in situ NMR circuit operating at 84 kHz (Larmor frequencies of (129)Xe and (1)H nuclear spins), (ii) <0.3 nm narrowed 200 W laser source, (iii) in situ high-resolution near-IR spectroscopy, (iv) thermoelectric temperature control, (v) retroreflection optics, and (vi) optomechanical alignment system. The rapid prototyping endowed by 3D printing dramatically reduces production time and expenses while allowing reproducibility and integration of “off-the-shelf” components and enables the concept of printing on demand. The utility of this SEOP setup is demonstrated here to obtain near-unity (129)Xe polarization values in a 0.5 L optical pumping cell, including ~74 ± 7% at 1000 Torr xenon partial pressure, a record value at such high Xe density. Values for the (129)Xe polarization exponential build-up rate [(3.63 ± 0.15) × 10(−2) min(−1)] and in-cell (129)Xe spin−lattice relaxation time (T(1) = 2.19 ± 0.06 h) for 1000 Torr Xe were in excellent agreement with the ratio of the gas-phase polarizations for (129)Xe and Rb (P(Rb) ~ 96%). Hyperpolarization-enhanced (129)Xe gas imaging was demonstrated with a spherical phantom following automated gas transfer from the polarizer. Taken together, these results support the development of a wide range of chemical, biochemical, material science, and biomedical applications

Comparative study of in situ N2 rotational Raman spectroscopy methods for probing energy thermalisation processes during spin-exchange optical pumping

Spin-exchange optical pumping (SEOP) has been widely used to produce enhancements in nuclear spin polarisation for hyperpolarised noble gases. However, some key fundamental physical processes underlying SEOP remain poorly understood, particularly in regards to how pump laser energy absorbed during SEOP is thermalised, distributed and dissipated. This study uses in situ ultra-low frequency Raman spectroscopy to probe rotational temperatures of nitrogen buffer gas during optical pumping under conditions of high resonant laser flux and binary Xe/N2 gas mixtures. We compare two methods of collecting the Raman scattering signal from the SEOP cell: a conventional orthogonal arrangement combining intrinsic spatial filtering with the utilisation of the internal baffles of the Raman spectrometer, eliminating probe laser light and Rayleigh scattering, versus a new in-line modular design that uses ultra-narrowband notch filters to remove such unwanted contributions. We report a ~23-fold improvement in detection sensitivity using the in-line module, which leads to faster data acquisition and more accurate real-time monitoring of energy transport processes during optical pumping. The utility of this approach is demonstrated via measurements of the local internal gas temperature (which can greatly exceed the externally measured temperature) as a function of incident laser power and position within the cell

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

XeNA: an automated ‘open-source’ 129Xe hyperpolarizer for clinical use

Here we provide a full report on the construction, components, and capabilities of our consortium’s “open-source” large-scale (~ 1 L/h) 129Xe hyperpolarizer for clinical, pre-clinical, and materials NMR/MRI (Nikolaou et al., Proc. Natl. Acad. Sci. USA, 110, 14150 (2013)). The ‘hyperpolarizer’ is automated and built mostly of off-the-shelf components; moreover, it is designed to be cost-effective and installed in both research laboratories and clinical settings with materials costing less than $125,000. The device runs in the xenon-rich regime (up to 1800 Torr Xe in 0.5 L) in either stopped-flow or single-batch mode—making cryo-collection of the hyperpolarized gas unnecessary for many applications. In-cell 129Xe nuclear spin polarization values of ~ 30%–90% have been measured for Xe loadings of ~ 300–1600 Torr. Typical 129Xe polarization build-up and T1 relaxation time constants were ~ 8.5 min and ~ 1.9 h respectively under our spin-exchange optical pumping conditions; such ratios, combined with near-unity Rb electron spin polarizations enabled by the high resonant laser power (up to ~ 200 W), permit such high PXe values to be achieved despite the high in-cell Xe densities. Importantly, most of the polarization is maintained during efficient HP gas transfer to other containers, and ultra-long 129Xe relaxation times (up to nearly 6 h) were observed in Tedlar bags following transport to a clinical 3 T scanner for MR spectroscopy and imaging as a prelude to in vivo experiments. The device has received FDA IND approval for a clinical study of chronic obstructive pulmonary disease subjects. The primary focus of this paper is on the technical/engineering development of the polarizer, with the explicit goals of facilitating the adaptation of design features and operative modes into other laboratories, and of spurring the further advancement of HP-gas MR applications in biomedicine

Fundamental studies and applications for the development of novel MRI contrast agents: Hyperpolarized xenon-129 and superparamagnetic iron oxide nanoparticles

Since its discovery in the mid-1950s, the phenomenon of nuclear magnetic resonance (NMR) has been recognized as a powerful, nondestructive analytical technique capable of probing the structure and dynamics of many systems-- ranging in size from simple organic molecules, through large biomolecular complexes, and even the tissues of the human body by use of magnetic resonance imaging (MRI). Indeed, MRI is perhaps the most well-known application of MR, and in the clinic, MRI is growing in popularity as an alternative to other imaging modalities such as computerized tomography (CT), positron emission tomography (PET), and x-ray, all of which rely on ionizing forms of radiation to generate images. Both NMR and MRI operate on the same physical principles as discussed in Chapter 1: the manipulation of populations of nuclear spins in different energy states using radiofrequency (rf) pulses. This dissertation work focuses on the development of two different types of MRI contrast agents: hyperpolarized 129Xe gas and superparamagnetic iron oxide nanoparticles (SPIONs). The largest `Achilles\u27 Heel\u27 of MR techniques is their inherent lack of detection sensitivity due to the exceedingly small magnitude of the nuclear spins, giving rise to small thermal polarizations. Chapter 2 reviews strategies for improving the MR spin polarization, and the following chapter focuses on the physics of one such strategy-- spin-exchange optical pumping (SEOP), which is used to prepare highly spin-polarized noble gases (e.g., 3He and 129Xe). SEOP is a two-step process whereby first, the electronic spins of an alkali metal vapor become polarized via the absorption of circularly-polarized resonant laser light, and second, the electronic spin polarization is transferred from the alkali metal atoms to the nuclear spins of the noble gas atoms via collisions; Chapter 4 discussed the experimental considerations and implementation of SEOP. Hyperpolarized noble gases prepared via SEOP have a wide variety of MR applications, reviewed in Chapter 5, including use in pulmonary MRI where the hyperpolarized noble gas provides contrast in the lung-space. The development of hyperpolarized 129Xe as contrast for pulmonary MRI has suffered on two fronts: firstly, due to the physics of SEOP, generating large volumes of highly spin-polarized gas is challenging, and secondly, the commercial devices used to perform SEOP and prepare the hyperpolarized gas, so-called `hyperpolarizers\u27, are expensive and proprietary, which has limited access to the technology to researchers and clinics. Chapter 7 discusses the design and construction of a fully automated, clinical-scale, `open-source\u27 129Xe hyperpolarizer with the purpose of developing an accessible, lower cost, mostly `off-the-shelf\u27 alternative to commercial polarizers. The hyperpolarizer operates at high Xe densities and provides high polarizations (i.e., ~90%, ~57%, ~50%, and ~30% at Xe partial pressures of ~300, ~500, ~760, and ~1570 torr, respectively) and currently is housed at Brigham and Women\u27s Hospital where it has received full FDA/IRB approval and is involved in in vivo pulmonary imaging studies. Preliminary developments and results from a second-generation 129Xe hyperpolarizer are discussed in Chapter 8 which includes improvements in the optical design, gas handling manifold, and SEOP oven. The `open-source\u27 hyperpolarizer design allow for greater access to hyperpolarized gas technology, and in time, as more laboratories adopt the design and expand upon it, a community of scientists and clinicians using hyperpolarized gas will grow and facilitate the sharing of ideas. The final SEOP-related chapter discusses fundamental studies of N2 temperatures during SEOP conducted in situ with Raman spectroscopy which shed light on the thermalization of energy during SEOP and the interrelation between key experimental SEOP parameters. The second aspect of MRI contrast discussed is the use of SPIONs as environmentally- sensitive contrast agents, and the synthesis and applications of SPIONs are reviewed in Chapter 6. Among other features, SPIONs offer high biological tolerability and flexible surface chemistry to allow for functionalization which can be exploited to yield differential MR response in different chemical environments. One general biological parameter of interest is tissue pH where local reductions in pH are associated with a variety of conditions including inflammation and cancers, and Chapter 10 focuses on the development of melamine dendron-functionalized SPIONs as pH-sensitive MRI contrast agents. Also discussed is a model for understanding how SPION clustering affects MR response. Such contrast agents could be developed as molecular imaging agents capable of mapping tumor pH in vivo

The clinical use of lung MRI in cystic fibrosis: what, now, how?

International audienceTo assess airway and lung parenchymal damage noninvasively in cystic fibrosis (CF), chest MRI has been historically out of the scope of routine clinical imaging because of technical difficulties such as low proton density and respiratory and cardiac motion. However, technological breakthroughs have emerged that dramatically improve lung MRI quality (including signal-to-noise ratio, resolution, speed, and contrast). At the same time, novel treatments have changed the landscape of CF clinical care. In this contemporary context, there is now consensus that lung MRI can be used clinically to assess CF in a radiation-free manner and to enable quantification of lung disease severity. MRI can now achieve three-dimensional, high-resolution morphologic imaging, and beyond this morphologic information, MRI may offer the ability to sensitively differentiate active inflammation vs scarring tissue. MRI could also characterize various forms of inflammation for early guidance of treatment. Moreover, functional information from MRI can be used to assess regional, small-airway disease with sensitivity to detect small changes even in patients with mild CF. Finally, automated quantification methods have emerged to support conventional visual analyses for more objective and reproducible assessment of disease severity. This article aims to review the most recent developments of lung MRI, with a focus on practical application and clinical value in CF, and the perspectives on how these modern techniques may converge and impact patient care soon

pH-Sensitive MR Responses Induced by Dendron-Functionalized SPIONs

We report a series of investigations of the pH-sensitive magnetic resonance (MR) responses of various surface-functionalized SPIONs (superparamagnetic iron oxide nanoparticles). First, functionalization of ~12 nm highly monocrystalline SPION cores with three different generations of melamine-dendrons was optimized to give agents with high molar relaxivities (e.g. ~300 mM·s at 7 T and ~20-30 mM·s at 0.5 T) and excellent aqueous stabilities. Molar relaxivities were found to exhibit great sensitivity to pH at physiologically-relevant ionic strengths, with sharp inflections observed at pH values near the p of the melamine monomer. The strength of the effect was observed to grow with increasing dendron generation (with concomitant shift in the position of the main pH inflection). Opposing behavior in and * trends may be exploited to provide a ratiometric MR response to pH. Combined with TEM and corresponding MR measurements from solutions of varying ionic strengths, these results are consistent with the pH-sensitive behavior originating from transient, reversible SPION clustering modulated by an interplay between SPION surface charge density and solution ionic strength. Studies of SPION cellular uptake and MR response in HeLa cell cultures are also presented. Finally, comparisons with the MR responses of SPIONs with alternative functionalities-derivatives of nitrilotriacetic acid or poly(1-vinylimidazole)-indicate that these types of pH-sensitive MR responses can be highly dependent upon the chemical composition of the surface species (and thus amenable to modulation through rational design)