Taxonomic Interference Associated with Phonemic Paraphasias in Agrammatic Primary Progressive Aphasia.

Phonemic paraphasias are thought to reflect phonological (post-semantic) deficits in language production. Here we present evidence that phonemic paraphasias in non-semantic primary progressive aphasia (PPA) may be associated with taxonomic interference. Agrammatic and logopenic PPA patients and control participants performed a word-to-picture visual search task where they matched a stimulus noun to 1 of 16 object pictures as their eye movements were recorded. Participants were subsequently asked to name the same items. We measured taxonomic interference (ratio of time spent viewing related vs. unrelated foils) during the search task for each item. Target items that elicited a phonemic paraphasia during object naming elicited increased taxonomic interference during the search task in agrammatic but not logopenic PPA patients. These results could reflect either very subtle sub-clinical semantic distortions of word representations or partial degradation of specific phonological word forms in agrammatic PPA during both word-to-picture matching (input stage) and picture naming (output stage). The mechanism for phonemic paraphasias in logopenic patients seems to be different and to be operative at the pre-articulatory stage of phonological retrieval. Glucose metabolic imaging suggests that degeneration in the left posterior frontal lobe and left temporo-parietal junction, respectively, might underlie these different patterns of phonemic paraphasia.

Resonant Inelastic X-Ray Scattering Reveals Hidden Local Transitions of the Aqueous OH Radical.

Resonant inelastic x-ray scattering (RIXS) provides remarkable opportunities to interrogate ultrafast dynamics in liquids. Here we use RIXS to study the fundamentally and practically important hydroxyl radical in liquid water, OH(aq). Impulsive ionization of pure liquid water produced a short-lived population of OH(aq), which was probed using femtosecond x-rays from an x-ray free-electron laser. We find that RIXS reveals localized electronic transitions that are masked in the ultraviolet absorption spectrum by strong charge-transfer transitions-thus providing a means to investigate the evolving electronic structure and reactivity of the hydroxyl radical in aqueous and heterogeneous environments. First-principles calculations provide interpretation of the main spectral features.

Nanosecond X-Ray Photon Correlation Spectroscopy on Magnetic Skyrmions.

We report an x-ray photon correlation spectroscopy method that exploits the recent development of the two-pulse mode at the Linac Coherent Light Source. By using coherent resonant x-ray magnetic scattering, we studied spontaneous fluctuations on nanosecond time scales in thin films of multilayered Fe/Gd that exhibit ordered stripe and Skyrmion lattice phases. The correlation time of the fluctuations was found to differ between the Skyrmion phase and near the stripe-Skyrmion boundary. This technique will enable a significant new area of research on the study of equilibrium fluctuations in condensed matter.

Evaluation of highly accelerated simultaneous multi-slice EPI for fMRI.

Echo planar imaging (EPI) is the MRI technique that is most widely used for blood oxygen level-dependent (BOLD) functional MRI (fMRI). Recent advances in EPI speed have been made possible with simultaneous multi-slice (SMS) methods which combine acceleration factors M from multiband (MB) radiofrequency pulses and S from simultaneous image refocusing (SIR) to acquire a total of N=S×M images in one echo train, providing up to N times speed-up in total acquisition time over conventional EPI. We evaluated accelerations as high as N=48 using different combinations of S and M which allow for whole brain imaging in as little as 100ms at 3T with a 32 channel head coil. The various combinations of acceleration parameters were evaluated by tSNR as well as BOLD contrast-to-noise ratio (CNR) and information content from checkerboard and movie clips in fMRI experiments. We found that at low acceleration factors (N≤6), setting S=1 and varying M alone yielded the best results in all evaluation metrics, while at acceleration N=8 the results were mixed using both S=1 and S=2 sequences. At higher acceleration factors (N>8), using S=2 yielded maximal BOLD CNR and information content as measured by classification of movie clip frames. Importantly, we found significantly greater BOLD information content using relatively fast TRs in the range of 300ms-600ms compared to a TR of 2s, suggesting that faster TRs capture more information per unit time in task based fMRI.

High resolution whole brain diffusion imaging at 7T for the Human Connectome Project.

Mapping structural connectivity in healthy adults for the Human Connectome Project (HCP) benefits from high quality, high resolution, multiband (MB)-accelerated whole brain diffusion MRI (dMRI). Acquiring such data at ultrahigh fields (7T and above) can improve intrinsic signal-to-noise ratio (SNR), but suffers from shorter T2 and T2(⁎) relaxation times, increased B1(+) inhomogeneity (resulting in signal loss in cerebellar and temporal lobe regions), and increased power deposition (i.e. specific absorption rate (SAR)), thereby limiting our ability to reduce the repetition time (TR). Here, we present recent developments and optimizations in 7T image acquisitions for the HCP that allow us to efficiently obtain high quality, high resolution whole brain in-vivo dMRI data at 7T. These data show spatial details typically seen only in ex-vivo studies and complement already very high quality 3T HCP data in the same subjects. The advances are the result of intensive pilot studies aimed at mitigating the limitations of dMRI at 7T. The data quality and methods described here are representative of the datasets that will be made freely available to the community in 2015.

Experimental demonstration of a soft x-ray self-seeded free-electron laser.

The Linac Coherent Light Source has added a self-seeding capability to the soft x-ray range using a grating monochromator system. We report the demonstration of soft x-ray self-seeding with a measured resolving power of 2000-5000, wavelength stability of 10(-4), and an increase in peak brightness by a factor of 2-5 across the photon energy range of 500-1000 eV. By avoiding the need for a monochromator at the experimental station, the self-seeded beam can deliver as much as 50-fold higher brightness to users.

Examination of weekly mammary parenchymal area by ultrasound, mammary mass, and composition in Holstein heifers reared on 1 of 3 diets from birth to 2 months of age.

Monitoring in vivo growth of mammary parenchyma (PAR) has historically been difficult, necessitating slaughter studies to measure PAR quantity. Advances in ultrasound (US) technology warrant revisiting its use as a noninvasive tool to monitor PAR growth in vivo. The level of nutrient intake during the first 2mo of life may affect measures of mammary growth and composition. Objectives were to examine the utility of US as an in vivo tool to quantify PAR cross-sectional area in Holstein heifers reared on 1 of 3 diets from birth to 2mo of age, assessing potential dietary effects; assess the relationships between weekly US measurements, teat length, manual palpation of PAR scores, and PAR mass at 2mo of age; and examine mammary composition in experimental animals. Holstein heifers (n=24; 41±1kg of initial body weight) from a single farm were randomly assigned to 1 of 3 milk replacers that differed in source and amount of fat. Milk replacer was fed at 660g of dry matter/d until weaning at 42 d. Heifers had ad libitum access to a common calf starter (20% crude protein) and water for the duration of the 56-d trial. Teat length and palpation scores were obtained weekly. A real-time B-mode US with a 7.5-MHz convex probe was used to examine 2-dimensional PAR area in all 4 glands of heifers once weekly from 2 to 3 d of age to harvest at 56 d. The left front and left rear glands were also examined by US 24h postharvest to validate final US measurements, and then bisected to produce a sagittal plane view of PAR for comparison with US images. Mass and composition of mammary gland tissue were determined at 8 wk using standard methodology. Over the course of this 8-wk trial, average teat length increased from 11 to 17mm. The PAR area started small (6.6±3.2mm(2) per gland) and increased to 42.1±2.5mm(2) per gland by the end of the trial. As anticipated, based on measurements obtained at slaughter, US measurements were more related to amount of PAR (r=0.74) than either teat length (r=0.34) or palpation scoring (r=0.63). Importantly, US is quantitative, whereas palpation scoring is subjective. Diet did not affect mass or composition of PAR in young heifers; total udder PAR mass averaged 1.40±0.80g. In conclusion, we showed that in heifers younger than 2mo of age, obtaining weekly PAR measurements via ultrasound is an effective quantitative tool for measuring changes in PAR area in vivo. Future studies may incorporate and expand upon the methods developed here to determine what quantitative evaluation of PAR in young heifers can reveal about milk production capacity.

Absolute pulse energy measurements of soft x-rays at the Linac Coherent Light Source.

This paper reports novel measurements of x-ray optical radiation on an absolute scale from the intense and ultra-short radiation generated in the soft x-ray regime of a free electron laser. We give a brief description of the detection principle for radiation measurements which was specifically adapted for this photon energy range. We present data characterizing the soft x-ray instrument at the Linac Coherent Light Source (LCLS) with respect to the radiant power output and transmission by using an absolute detector temporarily placed at the downstream end of the instrument. This provides an estimation of the reflectivity of all x-ray optical elements in the beamline and provides the absolute photon number per bandwidth per pulse. This parameter is important for many experiments that need to understand the trade-offs between high energy resolution and high flux, such as experiments focused on studying materials via resonant processes. Furthermore, the results are compared with the LCLS diagnostic gas detectors to test the limits of linearity, and observations are reported on radiation contamination from spontaneous undulator radiation and higher harmonic content.

Attosecond-pump attosecond-probe x-ray spectroscopy of liquid water.

Attosecond-pump/attosecond-probe experiments have long been sought as the most straightforward method for observing electron dynamics in real time. Although there has been much success with overlapped near-infrared femtosecond and extreme ultraviolet attosecond pulses combined with theory, true attosecond-pump/attosecond-probe experiments have been limited. We used a synchronized attosecond x-ray pulse pair from an x-ray free-electron laser to study the electronic response to valence ionization in liquid water through all x-ray attosecond transient absorption spectroscopy (AX-ATAS). Our analysis showed that the AX-ATAS response is confined to the subfemtosecond timescale, eliminating any hydrogen atom motion and demonstrating experimentally that the 1b1 splitting in the x-ray emission spectrum is related to dynamics and is not evidence of two structural motifs in ambient liquid water.

Effects of image reconstruction on fiber orientation mapping from multichannel diffusion MRI: reducing the noise floor using SENSE.

PURPOSE: To examine the effects of the reconstruction algorithm of magnitude images from multichannel diffusion MRI on fiber orientation estimation. THEORY AND METHODS: It is well established that the method used to combine signals from different coil elements in multichannel MRI can have an impact on the properties of the reconstructed magnitude image. Using a root-sum-of-squares approach results in a magnitude signal that follows an effective noncentral-χ distribution. As a result, the noise floor, the minimum measurable in the absence of any true signal, is elevated. This is particularly relevant for diffusion-weighted MRI, where the signal attenuation is of interest. RESULTS: In this study, we illustrate problems that such image reconstruction characteristics may cause in the estimation of fiber orientations, both for model-based and model-free approaches, when modern 32-channel coils are used. We further propose an alternative image reconstruction method that is based on sensitivity encoding (SENSE) and preserves the Rician nature of the single-channel, magnitude MR signal. We show that for the same k-space data, root-sum-of-squares can cause excessive overfitting and reduced precision in orientation estimation compared with the SENSE-based approach. CONCLUSION: These results highlight the importance of choosing the appropriate image reconstruction method for tractography studies that use multichannel receiver coils for diffusion MRI acquisition.

The eyes speak when the mouth cannot: Using eye movements to interpret omissions in primary progressive aphasia.

Though it may seem simple, object naming is a complex multistage process that can be impaired by lesions at various sites of the language network. Individuals with neurodegenerative disorders of language, known as primary progressive aphasias (PPA), have difficulty with naming objects, and instead frequently say "I don't know" or fail to give a vocal response at all, known as an omission. Whereas other types of naming errors (paraphasias) give clues as to which aspects of the language network have been compromised, the mechanisms underlying omissions remain largely unknown. In this study, we used a novel eye tracking approach to probe the cognitive mechanisms of omissions in the logopenic and semantic variants of PPA (PPA-L and PPA-S). For each participant, we identified pictures of common objects (e.g., animals, tools) that they could name aloud correctly, as well as pictures that elicited an omission. In a separate word-to-picture matching task, those pictures appeared as targets embedded among an array with 15 foils. Participants were given a verbal cue and tasked with pointing to the target, while eye movements were monitored. On trials with correctly-named targets, controls and both PPA groups ceased visual search soon after foveating the target. On omission trials, however, the PPA-S group failed to stop searching, and went on to view many foils "post-target". As further indication of impaired word knowledge, gaze of the PPA-S group was subject to excessive "taxonomic capture", such that they spent less time viewing the target and more time viewing related foils on omission trials. In contrast, viewing behavior of the PPA-L group was similar to controls on both correctly-named and omission trials. These results indicate that the mechanisms of omission in PPA differ by variant. In PPA-S, anterior temporal lobe degeneration causes taxonomic blurring, such that words from the same category can no longer be reliably distinguished. In PPA-L, word knowledge remains relatively intact, and omissions instead appear to be caused by downstream factors (e.g., lexical access, phonological encoding). These findings demonstrate that when words fail, eye movements can be particularly informative.

The Human Connectome Project: a data acquisition perspective.

The Human Connectome Project (HCP) is an ambitious 5-year effort to characterize brain connectivity and function and their variability in healthy adults. This review summarizes the data acquisition plans being implemented by a consortium of HCP investigators who will study a population of 1200 subjects (twins and their non-twin siblings) using multiple imaging modalities along with extensive behavioral and genetic data. The imaging modalities will include diffusion imaging (dMRI), resting-state fMRI (R-fMRI), task-evoked fMRI (T-fMRI), T1- and T2-weighted MRI for structural and myelin mapping, plus combined magnetoencephalography and electroencephalography (MEG/EEG). Given the importance of obtaining the best possible data quality, we discuss the efforts underway during the first two years of the grant (Phase I) to refine and optimize many aspects of HCP data acquisition, including a new 7T scanner, a customized 3T scanner, and improved MR pulse sequences.

Comparison between eight- and sixteen-channel TEM transceive arrays for body imaging at 7 T.

Eight- and sixteen-channel transceive stripline/TEM body arrays were compared at 7 T (297 MHz) both in simulation and experiment. Despite previous demonstrations of similar arrays for use in body applications, a quantitative comparison of the two configurations has not been undertaken to date. Results were obtained on a male pelvis for assessing transmit, signal to noise ratio, and parallel imaging performance and to evaluate local power deposition versus transmit B(1) (B(1) (+) ). All measurements and simulations were conducted after performing local B(1) (+) phase shimming in the region of the prostate. Despite the additional challenges of decoupling immediately adjacent coils, the sixteen-channel array demonstrated improved or nearly equivalent performance to the eight-channel array based on the evaluation criteria. Experimentally, transmit performance and signal to noise ratio were 22% higher for the sixteen-channel array while significantly increased reduction factors were achievable in the left-right direction for parallel imaging. Finite difference time domain simulations demonstrated similar results with respect to transmit and parallel imaging performance, however, a higher transmit efficiency advantage of 33% was predicted. Simulations at both 3 and 7 T verified the expected parallel imaging improvements with increasing field strength and showed that, for a specific B(1) (+) shimming strategy used, the sixteen-channel array exhibited lower local and global specific absorption rate for a given B(1) (+) .

Combined counter-maneuvers accelerate recovery from orthostatic hypotension in familial dysautonomia.

BACKGROUND: In patients with familial dysautonomia (FD), prominent orthostatic hypotension (OH) endangers cerebral perfusion. Supine repositioning or abdominal compression improves systolic and diastolic blood pressure (BPsys and BPdia). OBJECTIVE: To determine whether OH recovers faster with combined supine repositioning and abdominal compression than with supine repositioning alone. METHODS: In 9 patients with FD (17.8 ± 3.9 years) and 10 healthy controls (18.8 ± 5 years), we assessed 2-min averages of BPsys, BPdia, and heart rate (HR) during supine rest, standing, supine repositioning, another supine rest, second standing, and supine repositioning with abdominal compression by leg elevation and flexion. We determined BPsys- and BPdia-recovery-times as intervals from return to supine until BP reached values equivalent to each participant's 2-min average at supine rest minus two standard deviations. Differences in signal values and BP-recovery-times between groups and positions were assessed by ANOVA and post hoc testing (significance: P < 0.05). RESULTS: Patients with FD had pronounced OH that improved with supine repositioning. However, BP only reached supine rest values with additional abdominal compression. In controls, BP was stable during positional changes. Without abdominal compression, BP-recovery-times were longer in patients with FD than those in controls, but similar to control values with compression (BPsys: 83.7 ± 64.1 vs 36.6 ± 49.5 s; P = 0.013; BPdia: 84.6 ± 65.2 vs 35.3 ± 48.9 s; P = 0.009). CONCLUSION: Combining supine repositioning with abdominal compression significantly accelerates recovery from OH and thus lowers the risk of hypotension-induced cerebral hypoperfusion.

The fluctuation-dissipation measurement instrument at the Linac Coherent Light Source.

The development of new modes at x-ray free electron lasers has inspired novel methods for studying fluctuations at different energies and timescales. For closely spaced x-ray pulses that can be varied on ultrafast time scales, we have constructed a pair of advanced instruments to conduct studies targeting quantum materials. We first describe a prototype instrument built to test the proof-of-principle of resonant magnetic scattering using ultrafast pulse pairs. This is followed by a description of a new endstation, the so-called fluctuation-dissipation measurement instrument, which was used to carry out studies with a fast area detector. In addition, we describe various types of diagnostics for single-shot contrast measurements, which can be used to normalize data on a pulse-by-pulse basis and calibrate pulse amplitude ratios, both of which are important for the study of fluctuations in materials. Furthermore, we present some new results using the instrument that demonstrates access to higher momentum resolution.

Enhanced charge density wave coherence in a light-quenched, high-temperature superconductor.

Superconductivity and charge density waves (CDWs) are competitive, yet coexisting, orders in cuprate superconductors. To understand their microscopic interdependence, a probe capable of discerning their interaction on its natural length and time scale is necessary. We use ultrafast resonant soft x-ray scattering to track the transient evolution of CDW correlations in YBa2Cu3O6+x after the quench of superconductivity by an infrared laser pulse. We observe a nonthermal response of the CDW order characterized by a near doubling of the correlation length within ≈1 picosecond of the superconducting quench. Our results are consistent with a model in which the interaction between superconductivity and CDWs manifests inhomogeneously through disruption of spatial coherence, with superconductivity playing the dominant role in stabilizing CDW topological defects, such as discommensurations.

Coherence properties of individual femtosecond pulses of an x-ray free-electron laser.

Measurements of the spatial and temporal coherence of single, femtosecond x-ray pulses generated by the first hard x-ray free-electron laser, the Linac Coherent Light Source, are presented. Single-shot measurements were performed at 780 eV x-ray photon energy using apertures containing double pinholes in "diffract-and-destroy" mode. We determined a coherence length of 17 µm in the vertical direction, which is approximately the size of the focused Linac Coherent Light Source beam in the same direction. The analysis of the diffraction patterns produced by the pinholes with the largest separation yields an estimate of the temporal coherence time of 0.55 fs. We find that the total degree of transverse coherence is 56% and that the x-ray pulses are adequately described by two transverse coherent modes in each direction. This leads us to the conclusion that 78% of the total power is contained in the dominant mode.

Temporal variation in out-of-hospital cardiac arrest occurrence in individuals with or without diabetes.

OBJECTIVE: Out-of-hospital cardiac arrest (OHCA) occurrence has been shown to exhibit a circadian rhythm, following the circadian rhythm of acute myocardial infarction (AMI) occurrence. Diabetes mellitus (DM) is associated with changes in circadian rhythm. We aimed to compare the temporal variation of OHCA occurrence over the day and week between OHCA patients with DM and those without. METHODS: In two population-based OHCA registries (Amsterdam Resuscitation Studies [ARREST] 2010-2016, n = 4163, and Danish Cardiac Arrest Registry [DANCAR], 2010-2014, n = 12,734), adults (≥18y) with presumed cardiac cause of OHCA and available medical history were included. Single and double cosinor analysis was performed to model circadian variation of OHCA occurrence. Stratified analysis of circadian variation was performed in patients with AMI as immediate cause of OHCA. RESULTS: DM patients (22.8% in ARREST, 24.2% in DANCAR) were older and more frequently had cardiovascular risk factors or previous cardiovascular disease. Both cohorts showed 24 h-rhythmicity, with significant amplitudes in single and double cosinor functions (P-range < 0.001). In both registries, a morning peak (10:00-11:00) and an evening peak (20:00-21:00) was observed in both DM and non-DM patients. No septadian variation was observed in either DM or non-DM patients (P-range 0.13-84). CONCLUSIONS: In these two population-based OHCA registries, we observed a similar circadian rhythm of OHCA occurrence in DM and non-DM patients.

Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation.

Abdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizygous knockout mice (Col4a1/a2+/-, 129Svj background) we show that partial Col4a1/a2 deficiency augmented AAA formation. Although unchallenged aortas were morphometrically and biomechanically unaffected by genotype, explorative proteomic analyses of aortas revealed a clear reduction in BM components and contractile vascular smooth muscle cell (VSMC) proteins, suggesting a central effect of the BM in maintaining VSMCs in the contractile phenotype. These findings were translated to human arteries by showing that COL4A1/A2 correlated to BM proteins and VSMC markers in non-lesioned internal mammary arteries obtained from coronary artery bypass procedures. Moreover, in human AAA tissue, MYH11 (VSMC marker) was depleted in areas of reduced COL4 as assessed by immunohistochemistry. Finally, circulating COL4A1 degradation fragments correlated with AAA progression in the largest Danish AAA cohort, suggesting COL4A1/A2 proteolysis to be an important feature of AAA formation. In sum, we identify COL4A1/A2 as a critical regulator of VSMC phenotype and a protective factor in AAA formation.

Interaction of short x-ray pulses with low-Z x-ray optics materials at the LCLS free-electron laser.

Materials used for hard x-ray-free-electron laser (XFEL) optics must withstand high-intensity x-ray pulses. The advent of the Linac Coherent Light Source has enabled us to expose candidate optical materials, such as bulk B4C and SiC films, to 0.83 keV XFEL pulses with pulse energies between 1 µJ and 2 mJ to determine short-pulse hard x-ray damage thresholds. The fluence required for the onset of damage for single pulses is around the melt fluence and slightly lower for multiple pulses. We observed strong mechanical cracking in the materials, which may be due to the larger penetration depths of the hard x-rays.