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Purpose: To propose and validate an efficient method, based on a biophysically motivated signal model, for removing the orientation-dependent part of R 2 * 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 R 2 * . The estimated parameters were compared to the classical, mono-exponential decay model for R 2 * 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 R 2 * , it was compared to the established phenomenological method for separating R 2 * into orientation-dependent and -independent parts., Results: Using the phenomenological method on the classical signal model, the well-known separation of R 2 * 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 R 2 * using only a single GRE measurement., (© 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Parametric imaging methods (e.g., T 1 relaxation time mapping) have been shown to be more reproducible across time and vendors than weighted (e.g., T 1 -weighted) images. The purpose of this work was to more extensively evaluate the validity of this assertion., Methods: Seven volunteers underwent twice-repeated acquisitions of variable flip-angle T 1 mapping, including B 1 + calibration, on a 3T Philips Achieva and 3T Siemens Trio scanner. Intra-scanner and inter-vendor T 1 variability were calculated. To determine T 1 reproducibility levels in longitudinal settings, or after changing hardware or software, four additional data sets were acquired from two of the participants; one participant was scanned on a different 3T Siemens Trio scanner and another on the same 3T Philips Achieva scanner but after a software upgrade., Results: Intra-scanner variability of voxel-wise T 1 values was consistent between the two vendors, averaging 0.7/0.7/1.3/1.4% in white matter/cortical gray matter/subcortical gray matter/cerebellum, respectively. We observed, however, a systematic bias between the two vendors of https://doi.org/10.0/7.8/8.6/10.0%, respectively. The T 1 bias across two scanners of the same model was greater than intra-scanner variability, although still only at 1.4/1.0/1.9/2.3%, respectively. A greater bias was identified for data sets acquired before/after software upgrade in white matter/cortical gray matter (3.6/2.7%) whereas variability in subcortical gray matter/cerebellum was comparable (1.7/1.9%)., Conclusion: We established intra- and inter-vendor reproducibility levels for a widely used T 1 mapping protocol. We anticipate that these results will guide the design of multi-center studies, particularly those encompassing multiple vendors. Furthermore, this baseline level of reproducibility should be established or surpassed during the piloting phase of such studies., (© 2018 International Society for Magnetic Resonance in Medicine.)

Quantitative Susceptibility Mapping (QSM), best known as a surrogate for tissue iron content, is becoming a highly relevant MRI contrast for monitoring cellular and vascular status in aging, addiction, traumatic brain injury and, in general, a wide range of neurological disorders. In this study we present a new Bayesian QSM algorithm, named Multi-Scale Dipole Inversion (MSDI), which builds on the nonlinear Morphology-Enabled Dipole Inversion (nMEDI) framework, incorporating three additional features: (i) improved implementation of Laplace's equation to reduce the influence of background fields through variable harmonic filtering and subsequent deconvolution, (ii) improved error control through dynamic phase-reliability compensation across spatial scales, and (iii) scalewise use of the morphological prior. More generally, this new pre-conditioned QSM formalism aims to reduce the impact of dipole-incompatible fields and measurement errors such as flow effects, poor signal-to-noise ratio or other data inconsistencies that can lead to streaking and shadowing artefacts. In terms of performance, MSDI is the first algorithm to rank in the top-10 for all metrics evaluated in the 2016 QSM Reconstruction Challenge. It also demonstrated lower variance than nMEDI and more stable behaviour in scan-rescan reproducibility experiments for different MRI acquisitions at 3 and 7 Tesla. In the present work, we also explored new forms of susceptibility MRI contrast making explicit use of the differential information across spatial scales. Specifically, we show MSDI-derived examples of: (i) enhanced anatomical detail with susceptibility inversions from short-range dipole fields (hereby referred to as High-Pass Susceptibility Mapping or HPSM), (ii) high specificity to venous-blood susceptibilities for highly regularised HPSM (making a case for MSDI-based Venography or VenoMSDI), (iii) improved tissue specificity (and possibly statistical conditioning) for Macroscopic-Vessel Suppressed Susceptibility Mapping (MVSSM), and (iv) high spatial specificity and definition for HPSM-based Susceptibility-Weighted Imaging (HPSM-SWI) and related intensity projections., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Quantitative MRI (qMRI) provides surrogate brain maps of myelin and iron content. After spatial normalization to a common standard brain space, these may be used to detect altered myelination and iron accumulation in clinical populations. Here, volumetric and combined volumetric and surface-based (CVS) normalization were compared to identify which procedure would afford the greatest sensitivity to inter-regional differences (contrast), and the lowest inter-subject variability (under normal conditions), of myelin- and iron-related qMRI parameters, in whole-brain group-level studies. Ten healthy volunteers were scanned twice at 3 Tesla. Three-dimensional T1-weighted, T2-weighted and multi-parametric mapping sequences for brain qMRI were used to map myelin and iron content over the whole brain. Parameter maps were spatially normalized using volumetric (DARTEL) and CVS procedures. Tissue probability weighting and isotropic Gaussian smoothing were integrated in DARTEL for voxel-based quantification (VBQ). Contrasts, coefficients of variations and sensitivity to detecting differences in the parameters were estimated in standard space for each approach on region of interest (ROI) and voxel-by-voxel bases. The contrast between cortical and subcortical ROIs with respectively different myelin and iron content was higher following CVS, compared to DARTEL-VBQ, normalization. Across cortical voxels, the inter-individual variability of myelin and iron qMRI maps were comparable between CVS (with no smoothing) and DARTEL-VBQ (with smoothing). CVS normalization of qMRI maps preserves higher myelin and iron contrast than DARTEL-VBQ over the entire brain, while exhibiting comparable variability in the cerebral cortex without extra smoothing. Thus, CVS may prove useful for detecting small microstructural differences in whole-brain group-level qMRI studies., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Measuring the structural composition of the cortex is critical to understanding typical development, yet few investigations in humans have charted markers in vivo that are sensitive to tissue microstructural attributes. Here, we used a well-validated quantitative MR protocol to measure four parameters (R 1 , MT, R 2 *, PD*) that differ in their sensitivity to facets of the tissue microstructural environment (R 1 , MT: myelin, macromolecular content; R 2 *: myelin, paramagnetic ions, i.e., iron; PD*: free water content). Mapping these parameters across cortical regions in a young adult cohort (18-39 years, N = 93) revealed expected patterns of increased macromolecular content as well as reduced tissue water content in primary and primary adjacent cortical regions. Mapping across cortical depth within regions showed decreased expression of myelin and related processes - but increased tissue water content - when progressing from the grey/white to the grey/pial boundary, in all regions. Charting developmental change in cortical microstructure cross-sectionally, we found that parameters with sensitivity to tissue myelin (R 1 & MT) showed linear increases with age across frontal and parietal cortex (change 0.5-1.0% per year). Overlap of robust age effects for both parameters emerged in left inferior frontal, right parietal and bilateral pre-central regions. Our findings afford an improved understanding of ontogeny in early adulthood and offer normative quantitative MR data for inter- and intra-cortical composition, which may be used as benchmarks in further studies., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

We investigated the role of the left temporo-parietal regions in supporting reading abilities of 23 patients with central alexia (CA). For the behavioural data, we employed principal components analysis (PCA), which identified two components: 'reading aloud' and 'reading for meaning'. Voxel-based morphometry of the PCA results showed an association between reading aloud and grey matter density in the left supramarginal gyrus, part of the dorsal visual stream. By contrast, reading for meaning was associated with a large cluster in the left ventral visual stream, from the collateral sulcus to the anterior temporal pole. Most of the peaks were within the group lesion map, indicating that sparing of these areas results in better preservation of reading ability. However, one white matter (WM) cluster in the medial occipitotemporal lobe was outside the lesioned area. A post-hoc test demonstrated that WM density here was equivalent to controls, suggesting that this was not driven by lesion effects. The two likeliest explanations for this correlation are: 1) that pre-morbid, inter-individual differences in brain structure mitigate the effects of CA; 2) that post-morbid practice-based with reading caused compensatory plasticity. We hope to adjudicate between these explanations with longitudinal therapy data collected in this cohort., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The locus coeruleus (LC) is the principal origin of noradrenaline in the brain. LC integrity varies considerably across healthy older individuals, and is suggested to contribute to altered cognitive functions in aging. Here we test this hypothesis using an incidental memory task that is known to be susceptible to noradrenergic modulation. We used MRI neuromelanin (NM) imaging to assess LC structural integrity and pupillometry as a putative index of LC activation in both younger and older adults. We show that older adults with reduced structural LC integrity show poorer subsequent memory. This effect is more pronounced for emotionally negative events, in accord with a greater role for noradrenergic modulation in encoding salient or aversive events. In addition, we found that salient stimuli led to greater pupil diameters, consistent with increased LC activation during the encoding of such events. Our study presents novel evidence that a decrement in noradrenergic modulation impacts on specific components of cognition in healthy older adults. The findings provide a strong motivation for further investigation of the effects of altered LC integrity in pathological aging., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Magnetoencephalography (MEG) is a direct measure of neuronal current flow; its anatomical resolution is therefore not constrained by physiology but rather by data quality and the models used to explain these data. Recent simulation work has shown that it is possible to distinguish between signals arising in the deep and superficial cortical laminae given accurate knowledge of these surfaces with respect to the MEG sensors. This previous work has focused around a single inversion scheme (multiple sparse priors) and a single global parametric fit metric (free energy). In this paper we use several different source inversion algorithms and both local and global, as well as parametric and non-parametric fit metrics in order to demonstrate the robustness of the discrimination between layers. We find that only algorithms with some sparsity constraint can successfully be used to make laminar discrimination. Importantly, local t-statistics, global cross-validation and free energy all provide robust and mutually corroborating metrics of fit. We show that discrimination accuracy is affected by patch size estimates, cortical surface features, and lead field strength, which suggests several possible future improvements to this technique. This study demonstrates the possibility of determining the laminar origin of MEG sensor activity, and thus directly testing theories of human cognition that involve laminar- and frequency-specific mechanisms. This possibility can now be achieved using recent developments in high precision MEG, most notably the use of subject-specific head-casts, which allow for significant increases in data quality and therefore anatomically precise MEG recordings., Section: Analysis methods., Classifications: Source localization: inverse problem; Source localization: other., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

The ability to introspectively evaluate our experiences to form accurate metacognitive beliefs, or insight, is an essential component of decision-making. Previous research suggests individuals vary substantially in their level of insight, and that this variation is related to brain volume and function, particularly in the anterior prefrontal cortex (aPFC). However, the neurobiological mechanisms underlying these effects are unclear, as qualitative, macroscopic measures such as brain volume can be related to a variety of microstructural features. Here we leverage a high-resolution (800µm isotropic) multi-parameter mapping technique in 48 healthy individuals to delineate quantitative markers of in vivo histological features underlying metacognitive ability. Specifically, we examined how neuroimaging markers of local grey matter myelination and iron content relate to insight as measured by a signal-theoretic model of subjective confidence. Our results revealed a pattern of microstructural correlates of perceptual metacognition in the aPFC, precuneus, hippocampus, and visual cortices. In particular, we extend previous volumetric findings to show that right aPFC myeloarchitecture positively relates to metacognitive insight. In contrast, decreased myelination in the left hippocampus correlated with better metacognitive insight. These results highlight the ability of quantitative neuroimaging to reveal novel brain-behaviour correlates and may motivate future research on their environmental and developmental underpinnings., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

In magnetic resonance imaging, precise measurements of longitudinal relaxation time ( T 1 ) is crucial to acquire useful information that is applicable to numerous clinical and neuroscience applications. In this work, we investigated the precision of T 1 relaxation time as measured using the variable flip angle method with emphasis on the noise propagated from radiofrequency transmit field ([Formula: see text]) measurements. The analytical solution for T 1 precision was derived by standard error propagation methods incorporating the noise from the three input sources: two spoiled gradient echo (SPGR) images and a [Formula: see text] map. Repeated in vivo experiments were performed to estimate the total variance in T 1 maps and we compared these experimentally obtained values with the theoretical predictions to validate the established theoretical framework. Both the analytical and experimental results showed that variance in the [Formula: see text] map propagated comparable noise levels into the T 1 maps as either of the two SPGR images. Improving precision of the [Formula: see text] measurements significantly reduced the variance in the estimated T 1 map. The variance estimated from the repeatedly measured in vivo T 1 maps agreed well with the theoretically-calculated variance in T 1 estimates, thus validating the analytical framework for realistic in vivo experiments. We concluded that for T 1 mapping experiments, the error propagated from the [Formula: see text] map must be considered. Optimizing the SPGR signals while neglecting to improve the precision of the [Formula: see text] map may result in grossly overestimating the precision of the estimated T 1 values.

Speech articulation requires precise control of and coordination between the effectors of the vocal tract (e.g., lips, tongue, soft palate, and larynx). However, it is unclear how the cortex represents movements of and contact between these effectors during speech, or how these cortical responses relate to inter-regional anatomical borders. Here, we used phase-encoded fMRI to map somatomotor representations of speech articulations. Phonetically trained participants produced speech phones, progressing from front (bilabial) to back (glottal) place of articulation. Maps of cortical myelin proxies (R1 = 1/T1) further allowed us to situate functional maps with respect to anatomical borders of motor and somatosensory regions. Across participants, we found a consistent topological map of place of articulation, spanning the central sulcus and primary motor and somatosensory areas, that moved from lateral to inferior as place of articulation progressed from front to back. Phones produced at velar and glottal places of articulation activated the inferior aspect of the central sulcus, but with considerable across-subject variability. R1 maps for a subset of participants revealed that articulator maps extended posteriorly into secondary somatosensory regions. These results show consistent topological organization of cortical representations of the vocal apparatus in the context of speech behavior., (© The Author 2017. Published by Oxford University Press.)

How does human brain structure mature during adolescence? We used MRI to measure cortical thickness and intracortical myelination in 297 population volunteers aged 14-24 y old. We found and replicated that association cortical areas were thicker and less myelinated than primary cortical areas at 14 y. However, association cortex had faster rates of shrinkage and myelination over the course of adolescence. Age-related increases in cortical myelination were maximized approximately at the internal layer of projection neurons. Adolescent cortical myelination and shrinkage were coupled and specifically associated with a dorsoventrally patterned gene expression profile enriched for synaptic, oligodendroglial- and schizophrenia-related genes. Topologically efficient and biologically expensive hubs of the brain anatomical network had greater rates of shrinkage/myelination and were associated with overexpression of the same transcriptional profile as cortical consolidation. We conclude that normative human brain maturation involves a genetically patterned process of consolidating anatomical network hubs. We argue that developmental variation of this consolidation process may be relevant both to normal cognitive and behavioral changes and the high incidence of schizophrenia during human brain adolescence.

Traumatic spinal cord injury (SCI) has been shown to trigger structural atrophic changes within the spinal cord and brain. However, the relationship between structural changes and magnitude of neuropathic pain (NP) remains incompletely understood. Voxel-wise analysis of anatomical magnetic resonance imaging data provided information on cross-sectional cervical cord area and volumetric brain changes in 30 individuals with chronic traumatic SCI and 31 healthy controls. Participants were clinically assessed including neurological examination and pain questionnaire. Compared to controls, individuals with SCI exhibited decreased cord area, reduced grey matter (GM) volumes in anterior cingulate cortex (ACC), left insula, left secondary somatosensory cortex, bilateral thalamus, and decreased white matter volumes in pyramids and left internal capsule. The presence of NP was related with smaller cord area, increased GM in left ACC and right M1, and decreased GM in right primary somatosensory cortex and thalamus. Greater GM volume in M1 was associated with amount of NP. Below-level NP-associated structural changes in the spinal cord and brain can be discerned from trauma-induced consequences of SCI. The directionality of these relationships reveals specific changes across the neuroaxis (i.e., atrophic changes versus increases in volume) and may provide substrates of underlying neural mechanisms in the development of NP.

A pressing need exists to disentangle age-related changes from pathologic neurodegeneration. This study aims to characterize the spatial pattern and age-related differences of biologically relevant measures in vivo over the course of normal aging. Quantitative multiparameter maps that provide neuroimaging biomarkers for myelination and iron levels, parameters sensitive to aging, were acquired from 138 healthy volunteers (age range: 19-75 years). Whole-brain voxel-wise analysis revealed a global pattern of age-related degeneration. Significant demyelination occurred principally in the white matter. The observed age-related differences in myelination were anatomically specific. In line with invasive histologic reports, higher age-related differences were seen in the genu of the corpus callosum than the splenium. Iron levels were significantly increased in the basal ganglia, red nucleus, and extensive cortical regions but decreased along the superior occipitofrontal fascicle and optic radiation. This whole-brain pattern of age-associated microstructural differences in the asymptomatic population provides insight into the neurobiology of aging. The results help build a quantitative baseline from which to examine and draw a dividing line between healthy aging and pathologic neurodegeneration., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)