Mapping short association fibre connectivity up to V3 in the human brain in vivo.

Short association fibres (SAF) are the most abundant fibre pathways in the human white matter. Until recently, SAF could not be mapped comprehensively in vivo because diffusion weighted magnetic resonance imaging with sufficiently high spatial resolution needed to map these thin and short pathways was not possible. Recent developments in acquisition hardware and sequences allowed us to create a dedicated in vivo method for mapping the SAF based on sub-millimetre spatial resolution diffusion weighted tractography, which we validated in the human primary (V1) and secondary (V2) visual cortex against the expected SAF retinotopic order. Here, we extended our original study to assess the feasibility of the method to map SAF in higher cortical areas by including SAF up to V3. Our results reproduced the expected retinotopic order of SAF in the V2-V3 and V1-V3 stream, demonstrating greater robustness to the shorter V1-V2 and V2-V3 than the longer V1-V3 connections. The demonstrated ability of the method to map higher-order SAF connectivity patterns in vivo is an important step towards its application across the brain.

Improving MR axon radius estimation in human white matter using spiral acquisition and field monitoring.

PURPOSE: To compare MR axon radius estimation in human white matter using a multiband spiral sequence combined with field monitoring to the current state-of-the-art echo-planar imaging (EPI)-based approach. METHODS: A custom multiband spiral sequence was used for diffusion-weighted imaging at ultra-high b $$ b $$ -values. Field monitoring and higher order image reconstruction were employed to greatly reduce artifacts in spiral images. Diffusion weighting parameters were chosen to match a state-of-the art EPI-based axon radius mapping protocol. The spiral approach was compared to the EPI approach by comparing the image signal-to-noise ratio (SNR) and performing a test-retest study to assess the respective variability and repeatability of axon radius mapping. Effective axon radius estimates were compared over white matter voxels and along the left corticospinal tract. RESULTS: Increased SNR and reduced artifacts in spiral images led to reduced variability in resulting axon radius maps, especially in low-SNR regions. Test-retest variability was reduced by a factor of approximately 1.5 using the spiral approach. Reduced repeatability due to significant bias was found for some subjects in both spiral and EPI approaches, and attributed to scanner instability, pointing to a previously unknown limitation of the state-of-the-art approach. CONCLUSION: Combining spiral readouts with field monitoring improved mapping of the effective axon radius compared to the conventional EPI approach.

Quantitative MRI maps of human neocortex explored using cell type-specific gene expression analysis.

Quantitative magnetic resonance imaging (qMRI) allows extraction of reproducible and robust parameter maps. However, the connection to underlying biological substrates remains murky, especially in the complex, densely packed cortex. We investigated associations in human neocortex between qMRI parameters and neocortical cell types by comparing the spatial distribution of the qMRI parameters longitudinal relaxation rate (${R_{1}}$), effective transverse relaxation rate (${R_{2}}^{\ast }$), and magnetization transfer saturation (MTsat) to gene expression from the Allen Human Brain Atlas, then combining this with lists of genes enriched in specific cell types found in the human brain. As qMRI parameters are magnetic field strength-dependent, the analysis was performed on MRI data at 3T and 7T. All qMRI parameters significantly covaried with genes enriched in GABA- and glutamatergic neurons, i.e. they were associated with cytoarchitecture. The qMRI parameters also significantly covaried with the distribution of genes enriched in astrocytes (${R_{2}}^{\ast }$ at 3T, ${R_{1}}$ at 7T), endothelial cells (${R_{1}}$ and MTsat at 3T), microglia (${R_{1}}$ and MTsat at 3T, ${R_{1}}$ at 7T), and oligodendrocytes and oligodendrocyte precursor cells (${R_{1}}$ at 7T). These results advance the potential use of qMRI parameters as biomarkers for specific cell types.

B 1 + $$ {B}_1

PURPOSE: Magnetization transfer saturation ( MTsat $$ \mathrm{MTsat} $$ ) is a useful marker to probe tissue macromolecular content and myelination in the brain. The increased B 1 + $$ {B}_1^{+} $$ -inhomogeneity at ≥ 7 $$ \ge 7 $$ T and significantly larger saturation pulse flip angles which are often used for postmortem studies exceed the limits where previous MTsat $$ \mathrm{MTsat} $$ B 1 + $$ {B}_1^{+} $$ correction methods are applicable. Here, we develop a calibration-based correction model and procedure, and validate and evaluate it in postmortem 7T data of whole chimpanzee brains. THEORY: The B 1 + $$ {B}_1^{+} $$ dependence of MTsat $$ \mathrm{MTsat} $$ was investigated by varying the off-resonance saturation pulse flip angle. For the range of saturation pulse flip angles applied in typical experiments on postmortem tissue, the dependence was close to linear. A linear model with a single calibration constant C $$ C $$ is proposed to correct bias in MTsat $$ \mathrm{MTsat} $$ by mapping it to the reference value of the saturation pulse flip angle. METHODS: C $$ C $$ was estimated voxel-wise in five postmortem chimpanzee brains. "Individual-based global parameters" were obtained by calculating the mean C $$ C $$ within individual specimen brains and "group-based global parameters" by calculating the means of the individual-based global parameters across the five brains. RESULTS: The linear calibration model described the data well, though C $$ C $$ was not entirely independent of the underlying tissue and B 1 + $$ {B}_1^{+} $$ . Individual-based correction parameters and a group-based global correction parameter ( C = 1 . 2 $$ C=1.2 $$ ) led to visible, quantifiable reductions of B 1 + $$ {B}_1^{+} $$ -biases in high-resolution MTsat $$ \mathrm{MTsat} $$ maps. CONCLUSION: The presented model and calibration approach effectively corrects for B 1 + $$ {B}_1^{+} $$ inhomogeneities in postmortem 7T data.

Error quantification in multi-parameter mapping facilitates robust estimation and enhanced group level sensitivity.

Multi-Parameter Mapping (MPM) is a comprehensive quantitative neuroimaging protocol that enables estimation of four physical parameters (longitudinal and effective transverse relaxation rates R1 and R2*, proton density PD, and magnetization transfer saturation MTsat) that are sensitive to microstructural tissue properties such as iron and myelin content. Their capability to reveal microstructural brain differences, however, is tightly bound to controlling random noise and artefacts (e.g. caused by head motion) in the signal. Here, we introduced a method to estimate the local error of PD, R1, and MTsat maps that captures both noise and artefacts on a routine basis without requiring additional data. To investigate the method's sensitivity to random noise, we calculated the model-based signal-to-noise ratio (mSNR) and showed in measurements and simulations that it correlated linearly with an experimental raw-image-based SNR map. We found that the mSNR varied with MPM protocols, magnetic field strength (3T vs. 7T) and MPM parameters: it halved from PD to R1 and decreased from PD to MTsat by a factor of 3-4. Exploring the artefact-sensitivity of the error maps, we generated robust MPM parameters using two successive acquisitions of each contrast and the acquisition-specific errors to down-weight erroneous regions. The resulting robust MPM parameters showed reduced variability at the group level as compared to their single-repeat or averaged counterparts. The error and mSNR maps may better inform power-calculations by accounting for local data quality variations across measurements. Code to compute the mSNR maps and robustly combined MPM maps is available in the open-source hMRI toolbox.

Combining navigator and optical prospective motion correction for high-quality 500 µm resolution quantitative multi-parameter mapping at 7T.

PURPOSE: High-resolution quantitative multi-parameter mapping shows promise for non-invasively characterizing human brain microstructure but is limited by physiological artifacts. We implemented corrections for rigid head movement and respiration-related B0-fluctuations and evaluated them in healthy volunteers and dementia patients. METHODS: Camera-based optical prospective motion correction (PMC) and FID navigator correction were implemented in a gradient and RF-spoiled multi-echo 3D gradient echo sequence for mapping proton density (PD), longitudinal relaxation rate (R1) and effective transverse relaxation rate (R2*). We studied their effectiveness separately and in concert in young volunteers and then evaluated the navigator correction (NAVcor) with PMC in a group of elderly volunteers and dementia patients. We used spatial homogeneity within white matter (WM) and gray matter (GM) and scan-rescan measures as quality metrics. RESULTS: NAVcor and PMC reduced artifacts and improved the homogeneity and reproducibility of parameter maps. In elderly participants, NAVcor improved scan-rescan reproducibility of parameter maps (coefficient of variation decreased by 14.7% and 11.9% within WM and GM respectively). Spurious inhomogeneities within WM were reduced more in the elderly than in the young cohort (by 9% vs. 2%). PMC increased regional GM/WM contrast and was especially important in the elderly cohort, which moved twice as much as the young cohort. We did not find a significant interaction between the two corrections. CONCLUSION: Navigator correction and PMC significantly improved the quality of PD, R1, and R2* maps, particularly in less compliant elderly volunteers and dementia patients.

The variability of MR axon radii estimates in the human white matter.

The noninvasive quantification of axonal morphology is an exciting avenue for gaining understanding of the function and structure of the central nervous system. Accurate non-invasive mapping of micron-sized axon radii using commonly applied neuroimaging techniques, that is, diffusion-weighted MRI, has been bolstered by recent hardware developments, specifically MR gradient design. Here the whole brain characterization of the effective MR axon radius is presented and the inter- and intra-scanner test-retest repeatability and reproducibility are evaluated to promote the further development of the effective MR axon radius as a neuroimaging biomarker. A coefficient-of-variability of approximately 10% in the voxelwise estimation of the effective MR radius is observed in the test-retest analysis, but it is shown that the performance can be improved fourfold using a customized along-tract analysis.

Relating quantitative 7T MRI across cortical depths to cytoarchitectonics, gene expression and connectomics.

Ultra-high field MRI across the depth of the cortex has the potential to provide anatomically precise biomarkers and mechanistic insights into neurodegenerative disease like Huntington's disease that show layer-selective vulnerability. Here we compare multi-parametric mapping (MPM) measures across cortical depths for a 7T 500 µm whole brain acquisition to (a) layer-specific cell measures from the von Economo histology atlas, (b) layer-specific gene expression, using the Allen Human Brain atlas and (c) white matter connections using high-fidelity diffusion tractography, at a 1.3 mm isotropic voxel resolution, from a 300mT/m Connectom MRI system. We show that R2*, but not R1, across cortical depths is highly correlated with layer-specific cell number and layer-specific gene expression. R1- and R2*-weighted connectivity strength of cortico-striatal and intra-hemispheric cortical white matter connections was highly correlated with grey matter R1 and R2* across cortical depths. Limitations of the layer-specific relationships demonstrated are at least in part related to the high cross-correlations of von Economo atlas cell counts and layer-specific gene expression across cortical layers. These findings demonstrate the potential and limitations of combining 7T MPMs, gene expression and white matter connections to provide an anatomically precise framework for tracking neurodegenerative disease.

Mapping Short Association Fibers in the Early Cortical Visual Processing Stream Using In Vivo Diffusion Tractography.

Short association fibers (U-fibers) connect proximal cortical areas and constitute the majority of white matter connections in the human brain. U-fibers play an important role in brain development, function, and pathology but are underrepresented in current descriptions of the human brain connectome, primarily due to methodological challenges in diffusion magnetic resonance imaging (dMRI) of these fibers. High spatial resolution and dedicated fiber and tractography models are required to reliably map the U-fibers. Moreover, limited quantitative knowledge of their geometry and distribution makes validation of U-fiber tractography challenging. Submillimeter resolution diffusion MRI-facilitated by a cutting-edge MRI scanner with 300 mT/m maximum gradient amplitude-was used to map U-fiber connectivity between primary and secondary visual cortical areas (V1 and V2, respectively) in vivo. V1 and V2 retinotopic maps were obtained using functional MRI at 7T. The mapped V1-V2 connectivity was retinotopically organized, demonstrating higher connectivity for retinotopically corresponding areas in V1 and V2 as expected. The results were highly reproducible, as demonstrated by repeated measurements in the same participants and by an independent replication group study. This study demonstrates a robust U-fiber connectivity mapping in vivo and is an important step toward construction of a more complete human brain connectome.

Biophysically motivated efficient estimation of the spatially isotropic R2* component from a single gradient-recalled echo measurement.

PURPOSE: To propose and validate an efficient method, based on a biophysically motivated signal model, for removing the orientation-dependent part of R2* using a single gradient-recalled echo (GRE) measurement. METHODS: The proposed method utilized a temporal second-order approximation of the hollow-cylinder-fiber model, in which the parameter describing the linear signal decay corresponded to the orientation-independent part of R2* . The estimated parameters were compared to the classical, mono-exponential decay model for R2* in a sample of an ex vivo human optic chiasm (OC). The OC was measured at 16 distinct orientations relative to the external magnetic field using GRE at 7T. To show that the proposed signal model can remove the orientation dependence of R2* , it was compared to the established phenomenological method for separating R2* into orientation-dependent and -independent parts. RESULTS: Using the phenomenological method on the classical signal model, the well-known separation of R2* into orientation-dependent and -independent parts was verified. For the proposed model, no significant orientation dependence in the linear signal decay parameter was observed. CONCLUSIONS: Since the proposed second-order model features orientation-dependent and -independent components at distinct temporal orders, it can be used to remove the orientation dependence of R2* using only a single GRE measurement.

Microstructural imaging of human neocortex in vivo.

The neocortex of the human brain is the seat of higher brain function. Modern imaging techniques, chief among them magnetic resonance imaging (MRI), allow non-invasive imaging of this important structure. Knowledge of the microstructure of the neocortex has classically come from post-mortem histological studies of human tissue, and extrapolations from invasive animal studies. From these studies, we know that the scale of important neocortical structure spans six orders of magnitude, ranging from the size of axonal diameters (microns), to the size of cortical areas responsible for integrating sensory information (centimetres). MRI presents an opportunity to move beyond classical methods, because MRI is non-invasive and MRI contrast is sensitive to neocortical microstructure over all these length scales. MRI thus allows inferences to be made about neocortical microstructure in vivo, i.e. MRI-based in vivo histology. We review recent literature that has applied and developed MRI-based in vivo histology to probe the microstructure of the human neocortex, focusing specifically on myelin, iron, and neuronal fibre mapping. We find that applications such as cortical parcellation (using [Formula: see text] maps as proxies for myelin content) and investigation of cortical iron deposition with age (using [Formula: see text] maps) are already contributing to the frontiers of knowledge in neuroscience. Neuronal fibre mapping in the cortex remains challenging in vivo, but recent improvements in diffusion MRI hold promise for exciting applications in the near future. The literature also suggests that utilising multiple complementary quantitative MRI maps could increase the specificity of inferences about neocortical microstructure relative to contemporary techniques, but that further investment in modelling is required to appropriately combine the maps. In vivo histology of human neocortical microstructure is undergoing rapid development. Future developments will improve its specificity, sensitivity, and clinical applicability, granting an ever greater ability to investigate neuroscientific and clinical questions about the human neocortex.

Coexisting depressive symptoms do not limit the benefits of chronic neuromodulation: A study of over 200 patients.

AIMS: To examine the relationship between coexisting depressive symptoms and outcomes after staged neuromodulation procedures for refractory urological symptoms. METHODS: Adults who enrolled in a prospective database and completed a Personal Health Questionnaire Depression Scale (PHQ-8) at baseline were reviewed. The PHQ-8 and Generalized Anxiety Disorder (GAD-7) assessed depressive/anxiety symptoms pre and 6 months post device implant. Urological symptoms were assessed with The Interstitial Cystitis Symptom Index/Problem Index (ICSI-PI) and Overactive Bladder Questionnaire (OAB-q) at baseline, 3 and 6 months, and Global Response Assessments (GRA) post implant. Subjects, grouped by PHQ <10 and PHQ ≥10, were compared with Pearson's Chi-square, Fisher's Exact or Wilcoxon rank test, and Spearman's correlations. RESULTS: In 117 PHQ <10 and 84 PHQ ≥10 patients, age differed (mean 59 vs 52 years; P = 0.001), and PHQ <10 had lower GAD-7, ICSI-PI, and OAB-q scores at baseline (P < 0.0001, P = 0.0003, and P < 0.0008, respectively). Implantation rates were similar between groups. Reoperation and complication rates within the first 6 months did not differ, similar proportions (majority) were improved on the GRA at each time point, and ICSI-PI and OAB-q scores improved significantly. PHQ scores only improved significantly for those with baseline PHQ ≥10. Baseline PHQ strongly correlated with GAD-7 at baseline and 6 months, and baseline ICSI-PI. Change in PHQ positively correlated with the change in GAD-7, 6 month ICSI-PI, and change in ICSI-PI from baseline to 6 months. CONCLUSIONS: Coexisting depressive symptoms do not limit the efficacy of neuromodulation and PHQ improvements correlate with improved anxiety and bladder symptoms.

Patients with cancer and sepsis trials: an unfair representation?

Approximately 20% of sepsis cases are thought to occur in patients with cancer. Thus, such patients are an important cohort to be represented and characterised among sepsis trials. However, patients with cancer are commonly excluded from sepsis trials, although the extent to which is unknown. In this opinion article, we discuss our findings that suggest that patients with cancer are being under-represented in sepsis trials, often with an unclear rationale. We question the validity of generalising results from sepsis trials to heterogenous cancer populations and call for wider inclusion of patients with cancer to bridge this knowledge gap in sepsis management.

High-resolution quantitative and functional MRI indicate lower myelination of thin and thick stripes in human secondary visual cortex.

The characterization of cortical myelination is essential for the study of structure-function relationships in the human brain. However, knowledge about cortical myelination is largely based on post-mortem histology, which generally renders direct comparison to function impossible. The repeating pattern of pale-thin-pale-thick stripes of cytochrome oxidase (CO) activity in the primate secondary visual cortex (V2) is a prominent columnar system, in which histology also indicates different myelination of thin/thick versus pale stripes. We used quantitative magnetic resonance imaging (qMRI) in conjunction with functional magnetic resonance imaging (fMRI) at ultra-high field strength (7 T) to localize and study myelination of stripes in four human participants at sub-millimeter resolution in vivo. Thin and thick stripes were functionally localized by exploiting their sensitivity to color and binocular disparity, respectively. Resulting functional activation maps showed robust stripe patterns in V2 which enabled further comparison of quantitative relaxation parameters between stripe types. Thereby, we found lower longitudinal relaxation rates (R1) of thin and thick stripes compared to surrounding gray matter in the order of 1-2%, indicating higher myelination of pale stripes. No consistent differences were found for effective transverse relaxation rates (R2*). The study demonstrates the feasibility to investigate structure-function relationships in living humans within one cortical area at the level of columnar systems using qMRI.

Brain structure and function: a multidisciplinary pipeline to study hominoid brain evolution.

To decipher the evolution of the hominoid brain and its functions, it is essential to conduct comparative studies in primates, including our closest living relatives. However, strong ethical concerns preclude in vivo neuroimaging of great apes. We propose a responsible and multidisciplinary alternative approach that links behavior to brain anatomy in non-human primates from diverse ecological backgrounds. The brains of primates observed in the wild or in captivity are extracted and fixed shortly after natural death, and then studied using advanced MRI neuroimaging and histology to reveal macro- and microstructures. By linking detailed neuroanatomy with observed behavior within and across primate species, our approach provides new perspectives on brain evolution. Combined with endocranial brain imprints extracted from computed tomographic scans of the skulls these data provide a framework for decoding evolutionary changes in hominin fossils. This approach is poised to become a key resource for investigating the evolution and functional differentiation of hominoid brains.

From hypercalciuria to hypocitraturia--a shifting trend in pediatric urolithiasis?

PURPOSE: We analyzed the metabolic abnormalities in children with urolithiasis, and the relationship between diet and hypocitraturia. MATERIALS AND METHODS: A single center, retrospective analysis was conducted in all children with renal and/or ureteral calculi seen at our Multidisciplinary Stone Clinic between January 2010 and July 2011. Data at presentation were extracted from the clinical database. RESULTS: We analyzed 63 children (37 girls) with urolithiasis with a mean age of 13.43 ± 4.61 years. Of the 45 patients with 24-hour urinalysis, a metabolic risk factor was present in 68.9%, with hypocitraturia (58.1%) and hypercalciuria (48.3%) being the most common. Children with isolated hypocitraturia had lower urinary magnesium and potassium levels (1.06 ± 0.62 mg/kg and 0.53 ± 0.24 mmol/kg per day) than those with no metabolic abnormalities (1.72 ± 0.61 mg/kg and 0.68 ± 0.20 mmol/kg per day) (p = 0.015 and p = 0.132, respectively). Urinary citrate was positively correlated with urinary potassium (r = 0.50, p = 0.002) and urinary magnesium (r = 0.49, p = 0.001). Dietary analysis revealed a lower intake of magnesium and potassium in children with hypocitraturia (28.97% ± 12.25% and 15.42% ± 7.25% recommended dietary index) than in normocitraturic cases (51.06% ± 17.51% and 45.23% ± 29.49% recommended dietary index) (p = 0.042 and p = 0.056, respectively). CONCLUSIONS: The majority of children had an identifiable metabolic risk factor for urolithiasis, with hypocitraturia being the most common. This shift in metabolic trend may be a significant contributor to the increasing incidence in pediatric urolithiasis. Hypocitraturia appears to be dietary in origin, correlated with a low consumption of potassium and magnesium.

Quantum mechanical simulation of solid effect dynamic nuclear polarisation using Krylov-Bogolyubov time averaging and a restricted state-space.

A strategy is described for simulations of solid effect dynamic nuclear polarisation that reduces substantially the dimension of the quantum mechanical problem. Averaging the Hamiltonian in the doubly rotating frame is used to confine the active space to the zero quantum coherence subspace. A further restriction of the Liouville space is made by truncating higher spin order states, which are weakly populated due to the presence of relaxation processes. Based on a dissipative transport equation, which is used to estimate the transport of the magnetisation starting from single spin order to higher spin order states, a minimal spin order for the states is calculated that needs to be taken into account for the spin dynamics simulation. The strategy accelerates individual spin calculations by orders of magnitude, thus making it possible to simulate the polarisation dynamics of systems with up to 25 nuclear spins.

Parallel density matrix propagation in spin dynamics simulations.

Several methods for density matrix propagation in parallel computing environments are proposed and evaluated. It is demonstrated that the large communication overhead associated with each propagation step (two-sided multiplication of the density matrix by an exponential propagator and its conjugate) may be avoided and the simulation recast in a form that requires virtually no inter-thread communication. Good scaling is demonstrated on a 128-core (16 nodes, 8 cores each) cluster.

On the accuracy of the state space restriction approximation for spin dynamics simulations.

We present an algebraic foundation for the state space restriction approximation in spin dynamics simulations and derive applicability criteria as well as minimal basis set requirements for practically encountered simulation tasks. The results are illustrated with nuclear magnetic resonance (NMR), electron spin resonance (ESR), dynamic nuclear polarization (DNP), and spin chemistry simulations. It is demonstrated that state space restriction yields accurate results in systems where the time scale of spin relaxation processes approximately matches the time scale of the experiment. Rigorous error bounds and basis set requirements are derived.

Leading the integration of physician associates into the UK health workforce.

The introduction of physician associates into the UK health workforce is one of the most significant examples of potentially disruptive innovation in many years, and lessons can be learned from research into the introduction of advanced nurse practitioners. Positive, forward-looking health-care leadership is required at all levels to ensure the successful integration of physician associates into the UK workforce. This review found that organizational culture had an enormous impact on the introduction of advanced nurse practitioners and likewise will affect the integration of physician associates. The most effective strategies facilitated interprofessional, collaborative, collective and inclusive leadership and promoted high staff engagement, the development of proficient interprofessional practitioners, and a clear vision for collaborative practice. In terms of physician associates, such an approach will improve interprofessional and collaborative practice and create the supportive, motivated environment needed to facilitate the introduction of physician associates.