High-resolution diffusion-weighted imaging at 7 Tesla: single-shot readout trajectories and their impact on signal-to-noise ratio, spatial resolution and accuracy

Diffusion MRI (dMRI) is a valuable imaging technique to study the brain in vivo. However, the resolution of dMRI is limited by the low signal-to-noise ratio (SNR) of this technique. Various acquisition strategies have been developed to achieve high resolutions, but they require long scan times. Imaging at ultra-high fields (UHF) could further increase the SNR of single-shot dMRI; however, the shorter T2* and the greater field non-uniformities will degrade image quality. In this study, we investigated the trade-off between the SNR and resolution of different k-space trajectories, including echo planar imaging (EPI), partial Fourier EPI, and spiral, over a range of resolutions at 7T. The effective resolution, spatial specificity and sharpening effect were measured from the point spread function (PSF) of the simulated diffusion sequences for a nominal resolution range of 0.6-1.8 mm. In-vivo scans were acquired using the three readout trajectories. Field probes were used to measure dynamic magnetic fields up to the 3rd order of spherical harmonics. Using a static field map and the measured trajectories image artifacts were corrected, leaving T2* effects as the primary source of blurring. The effective resolution was examined in fractional anisotropy (FA) maps. In-vivo scans were acquired to calculate the SNR. EPI trajectories had the highest specificity, effective resolution, and image sharpening effect, but also had substantially lower SNR. Spirals had significantly higher SNR, but lower specificity. Line plots of the in-vivo scans in phase and frequency encode directions showed ~0.2 units difference in FA values between the different trajectories. The difference between the effective and nominal resolution is greater for spirals than for EPI. However, the higher SNR of spiral trajectories at UHFs allows us to achieve higher effective resolutions compared to EPI and PF-EPI trajectories

Up the leash: Exploring canine handlers’ perceptions of volunteering in canine-assisted interventions

To date, research on university and college based canine-assisted interventions for post-secondary students have focused on identifying the effects of spending time with therapy dogs on the well-being of participants and, to a lesser extent, exploring the effects of canine-assisted interventions on therapy dogs as a means of safeguarding canine welfare. Little empirical attention has focused on understanding the experience of volunteer canine handlers – agents at the heart of the success of canine-assisted interventions. The aim of this exploratory research was to first capture the voice of these key stakeholders to better understand their experience as canine handler volunteers and second to provide preliminary insights into their well-being. Sixty volunteer handlers with varying volunteer experience with a canine therapy program at a mid-size Canadian university responded to a series of open-ended prompts related to their volunteer work and completed a battery of well-being measures. Qualitative findings revealed that most participants identified social benefits to volunteering for themselves (64%) and for their dog (55%). The perceived impact on students (33%) and the ability to help university students (36%) were the most rewarding aspects of volunteering. Though enticed to volunteer by qualities of the CAI program (36%), participant motivations to continue volunteering were predominantly associated with personal benefits of volunteering (44%). Most handlers reported no challenges associated with volunteering (73%) and described their dog as happy after sessions (71%). Participants commonly described good therapy dogs as relaxed, calm, and respectful (66%) and strong handlers as having good awareness of their dog (48%). Quantitative findings revealed volunteer handlers reported elevated levels of positive affect (p = < 0.001, d = 1.19), greater satisfaction with life (p = < 0.001, d = 0.85) and lower levels of avoidant attachment to their therapy dog (p = < 0.001, d = -1.16) when compared to normative samples. Implications for the governing of university and college based programs and handler well-being are discussed

Optimization of acquisition parameters for cortical inhomogeneous magnetization transfer (ihMT) imaging using a rapid gradient echo readout

Purpose: Imaging biomarkers with increased myelin specificity are needed to better understand the complex progression of neurological disorders. Inhomogeneous magnetization transfer (ihMT) imaging is an emergent technique that has a high degree of specificity for myelin content but suffers from low signal-to-noise ratio (SNR). This study used simulations to determine optimal sequence parameters for ihMT imaging for use in high-resolution cortical mapping. Methods: MT-weighted cortical image intensity and ihMT SNR were simulated using modified Bloch equations for a range of sequence parameters. The acquisition time was limited to 4.5 min/volume. A custom MT-weighted RAGE sequence with center-out k-space encoding was used to enhance SNR at 3 Tesla. Pulsed MT imaging was studied over a range of saturation parameters and the impact of the turbo-factor on effective ihMT was investigated. 1 mm isotropic ihMTsat maps were generated in 25 healthy adults using an optimized protocol. Results: Greater SNR was observed for larger number of bursts consisting of 6-8 saturation pulses each, combined with a high readout turbo-factor. However, that protocol suffered from a point spread function that was more than twice the nominal resolution. For high-resolution cortical imaging, we selected a protocol with a higher effective resolution at the cost of a lower SNR. We present the first group-average ihMTsat whole-brain map at 1 mm isotropic resolution. Conclusion: This study presents the impact of saturation and excitation parameters on ihMTsat SNR and resolution. We demonstrate the feasibility of high-resolution cortical myelin imaging using ihMTsat in less than 20 minutes

Correcting for T1 bias in Magnetization Transfer Saturation (MTsat) Maps Using Sparse-MP2RAGE

Purpose: Magnetization transfer saturation (MTsat) mapping is commonly used to examine the macromolecular content of brain tissue. This study compared variable flip angle (VFA) T1 mapping against compressed sensing (cs)MP2RAGE T1 mapping for accelerating MTsat imaging. Methods: VFA, MP2RAGE and csMP2RAGE were compared against inversion recovery (IR) T1 in a phantom at 3 Tesla. The same 1 mm VFA, MP2RAGE and csMP2RAGE protocols were acquired in four healthy subjects to compare the resulting T1 and MTsat. Bloch-McConnell simulations were used to investigate differences between the phantom and in vivo T1 results. Finally, ten healthy controls were imaged twice with the csMP2RAGE MTsat protocol to quantify repeatability. Results: The MP2RAGE and csMP2RAGE protocols were 13.7% and 32.4% faster than the VFA protocol, respectively. All approaches provided accurate T1 values (<5% difference) in the phantom, but the accuracy of the T1 times was more impacted by differences in T2 for VFA than for MP2RAGE. In vivo, VFA generated longer T1 times than MP2RAGE and csMP2RAGE. Simulations suggest that the bias in the T1 values between VFA and IR-based approaches (MP2RAGE and IR) could be explained by the MT-effects from the inversion pulse. In the test-retest experiment, we found that the csMP2RAGE has a minimum detectable change of 3% for T1 mapping and 7.9% for MTsat imaging. Conclusions: We demonstrated that csMP2RAGE can be used in place of VFA T1 mapping in an MTsat protocol. Furthermore, a shorter scan time and high repeatability can be achieved using the csMP2RAGE sequence.Comment: 23 pages, 7 figures, 2 table

When Therapy Dogs Provide Virtual Comfort: Exploring University Students’ Insights and Perspectives

With the proliferation of canine-assisted interventions and the emphasis placed on the impact of these sessions in bolstering the well-being of visitors to sessions, especially university students, it can be easy to overlook just how participating in one of these sessions is experienced by participants. Capturing participants’ experiences is important as this holds the potential to inform program design and delivery and elucidate mechanisms within the intervention that were found to be especially efficacious. Forging new empirical terrain, this study explored the insights and perceptions of 469 undergraduate students who participated in a virtual canine-assisted stress-reduction intervention at a mid-size western Canadian university. Participants were randomly assigned to synchronous or asynchronous and dog or no-dog conditions and were asked to share their views of their experience by rating statements and responding to open-ended prompts. Thematic content analysis of findings revealed that a virtual canine-assisted intervention was well received by participants. Participants in the synchronous condition with a dog reported more favorable well-being benefits, as compared with participants in the asynchronous condition with a dog and with participants in both the synchronous and asynchronous conditions without a dog. Implications of these findings hold relevance for supporting geographically remote students and students for whom attending virtual sessions is the only option given barriers preventing them from in-person attendance. Correspondingly, considerations of the role of the handler and of animal welfare are presented

Dual-encoded magnetization transfer and diffusion imaging and its application to tract-specific microstructure mapping

We present a novel dual-encoded magnetization transfer (MT) and diffusion-weighted sequence and demonstrate its potential to resolve distinct properties of white matter fiber tracts at the sub-voxel level. The sequence was designed and optimized for maximal MT contrast efficiency. The resulting whole brain 2.6 mm isotropic protocol to measure tract-specific MT ratio (MTR) has a scan time under 7 minutes. Ten healthy subjects were scanned twice to assess repeatability. Two different analysis methods were contrasted: a technique to extract tract-specific MTR using Convex Optimization Modeling for Microstructure Informed Tractography (COMMIT), a global optimization technique; and conventional MTR tractometry. The results demonstrate that the tract-specific method can reliably resolve the MT ratios of major white matter fiber pathways and is less affected by partial volume effects than conventional multi-modal tractometry. Dual-encoded MT and diffusion is expected to both increase the sensitivity to microstructure alterations of specific tracts due to disease, ageing or learning, as well as lead to weighted structural connectomes with more anatomical specificity.Comment: 26 pages, 7 figure

Partial Deletion of Chromosome 8 β-defensin Cluster Confers Sperm Dysfunction and Infertility in Male Mice

β-defensin peptides are a family of antimicrobial peptides present at mucosal surfaces, with the main site of expression under normal conditions in the male reproductive tract. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. We show here that homozygous deletion of a cluster of nine β-defensin genes (DefbΔ9) in the mouse results in male sterility. The sperm derived from the mutants have reduced motility and increased fragility. Epididymal sperm isolated from the cauda should require capacitation to induce the acrosome reaction but sperm from the mutants demonstrate precocious capacitation and increased spontaneous acrosome reaction compared to wild-types but have reduced ability to bind the zona pellucida of oocytes. Ultrastructural examination reveals a defect in microtubule structure of the axoneme with increased disintegration in mutant derived sperm present in the epididymis cauda region, but not in caput region or testes. Consistent with premature acrosome reaction, sperm from mutant animals have significantly increased intracellular calcium content. Thus we demonstrate in vivo that β-defensins are essential for successful sperm maturation, and their disruption leads to alteration in intracellular calcium, inappropriate spontaneous acrosome reaction and profound male infertility

High spatial overlap but diverging age-related trajectories of cortical magnetic resonance imaging markers aiming to represent intracortical myelin and microstructure

ABSTRACT: Statistical effects of cortical metrics derived from standard T1- and T2-weighted magnetic resonance imaging (MRI) images, such as gray–white matter contrast (GWC), boundary sharpness coefficient (BSC), T1-weighted/T2-weighted ratio (T1w/T2w), and cortical thickness (CT), are often interpreted as representing or being influenced by intracortical myelin content with little empirical evidence to justify these interpretations. We first examined spatial correspondence with more biologically specific microstructural measures, and second compared between-marker age-related trends with the underlying hypothesis that different measures primarily driven by similar changes in myelo- and microstructural underpinnings should be highly related. Cortical MRI markers were derived from MRI images of 127 healthy subjects, aged 18–81, using cortical surfaces that were generated with the CIVET 2.1.0 pipeline. Their gross spatial distributions were compared with gene expression-derived cell-type densities, histology-derived cytoarchitecture, and quantitative R1 maps acquired on a subset of participants. We then compared between-marker age-related trends in their shape, direction, and spatial distribution of the linear age effect. The gross anatomical distributions of cortical MRI markers were, in general, more related to myelin and glial cells than neuronal indicators. Comparing MRI markers, our results revealed generally high overlap in spatial distribution (i.e., group means), but mostly divergent age trajectories in the shape, direction, and spatial distribution of the linear age effect. We conclude that the microstructural properties at the source of spatial distributions of MRI cortical markers can be different from microstructural changes that affect these markers in aging

Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006)

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease