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Cerebral folate transport deficiency, caused by a genetic defect in folate receptor α, is a devastating neurometabolic disorder that, if untreated, leads to epileptic encephalopathy, psychomotor decline and hypomyelination. Currently, there are limited data on effective dosage and duration of treatment, though early diagnosis and therapy with folinic acid appears critical. The aim of this long-term study was to identify new therapeutic approaches and novel biomarkers for assessing efficacy, focusing on myelin-sensitive MRI. Clinical, biochemical, structural and quantitative MRI parameters of seven patients with genetically confirmed folate receptor α deficiency were acquired over 13 years. Multimodal MRI approaches comprised MR-spectroscopy (MRS), magnetization transfer (MTI) and diffusion tensor imaging (DTI) sequences. Patients started oral treatment immediately following diagnosis or in an interval of up to 2.5 years. Escalation to intravenous and intrathecal administration was performed in the absence of effects. Five patients improved, one with a presymptomatic start of therapy remained symptom-free, and one with inconsistent treatment deteriorated. While CSF 5-methyltetrahydrofolate and MRS parameters normalized immediately after therapy initiation, myelin-sensitive MTI and DTI measures correlated with gradual clinical improvement and ongoing myelination under therapy. Early initiation of treatment at sufficient doses, considering early intrathecal applications, is critical for favorable outcome. The majority of patients showed clinical improvements that correlated best with MTI parameters, allowing individualized monitoring of myelination recovery. Presymptomatic therapy seems to ensure normal development and warrants newborn screening. Furthermore, the quantitative parameters of myelin-sensitive MRI for therapy assessments can now be used for hypomyelination disorders in general., (© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Dynamic glucose-enhanced (DGE) MRI is used to study the signal intensity time course (tissue response curve) after D-glucose injection. D-glucose has potential as a biodegradable alternative or complement to gadolinium-based contrast agents, with DGE being comparable with dynamic contrast-enhanced (DCE) MRI. However, the tissue uptake kinetics as well as the detection methods of DGE differ from DCE MRI, and it is relevant to compare these techniques in terms of spatiotemporal enhancement patterns. This study aims to develop a DGE analysis method based on tissue response curve shapes, and to investigate whether DGE MRI provides similar or complementary information to DCE MRI. Eleven patients with suspected gliomas were studied. Tissue response curves were measured for DGE and DCE MRI at 7 T and the area under the curve (AUC) was assessed. Seven types of response curve shapes were postulated and subsequently identified by deep learning to create color-coded "curve maps" showing the spatial distribution of different curve types. DGE AUC values were significantly higher in lesions than in normal tissue (p < 0.007). Furthermore, the distribution of curve types differed between lesions and normal tissue for both DGE and DCE. The DGE and DCE response curves in a 6-min postinjection time interval were classified as the same curve type in 20% of the lesion voxels, which increased to 29% when a 12-min DGE time interval was considered. While both DGE and DCE tissue response curve-shape analysis enabled differentiation of lesions from normal brain tissue in humans, their enhancements were neither temporally identical nor confined entirely to the same regions. Curve maps can provide accessible and intuitive information about the shape of DGE response curves, which is expected to be useful in the continued work towards the interpretation of DGE uptake curves in terms of D-glucose delivery, transport, and metabolism., (© 2022 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Purpose: To map T 1 and the local flip angle ( B 1 + ) in human brain using a single MP3RAGE sequence with 3 rapid acquisitions of gradient echoes (RAGEs)., Theory and Methods: A third RAGE with a relatively high flip angle was appended to an MP2RAGE sequence. Through curve fitting and a rational approximation for small flip angles and short TR, closed form solutions for T 1 and B 1 + were derived. The influence of different k-space encoding schemes on precision and whether edge enhancement artifacts could be reduced with a saturation pulse applied prior to the third RAGE were explored. Validation of T 1 estimates was performed using single-slice inversion recovery (IR) and a subsequent region-of-interest-based comparison, whereas validation of B 1 + was performed using a whole brain pixelwise comparison to a DREAM flip angle mapping protocol. Lastly, MP3RAGE was compared to T 1 -mapping by MP2RAGE with separate B 1 + correction., Results: Whole brain maps of T 1 and B 1 + at 1 mm isotropic resolution were obtained with MP3RAGE in 06:37 min. A linear-reverse centric-reverse centric phase-encoding order of the 3 RAGEs improved precision, and artifacts were successfully reduced with the saturation pulse. Estimations of T 1 and B 1 + deviated +2.5 ± 3.1% and -1.7 ± 8.6% from their respective references., Conclusion: T 1 and B 1 + can be mapped simultaneously using MP3RAGE. The approach can be thought of as combining MP2RAGE with a dual flip angle T 1 -mapping protocol. Both maps can be solved for analytically and will be inherently co-registered at the high resolution associated with MPRAGE., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background and Purpose: Cerebral tissue oxygenation is a critical brain viability parameter, and the magnetic properties of hemoglobin offer the opportunity to noninvasively quantify oxygen extraction fraction (OEF) by magnetic resonance imaging (MRI). Ultrahigh-field MRI shows advantages such as increased sensitivity to magnetic susceptibility differences and improved signal-to-noise ratio that can be translated into smaller voxel size, but also increased sensitivity to static and B1 field inhomogeneities. The aim was to produce a systematic comparison of three MRI-based methods for estimation of OEF., Methods: OEF estimates in 16 healthy subjects were obtained at 7T utilizing susceptometry-based oximetry (SBO), quantitative susceptibility mapping (QSM), and transverse relaxation rate (R2*). Two major draining veins, that is, the superior sagittal sinus (SSS) and the straight sinus (SS), were investigated, including mutual agreement between the methods in each of the two different vessels, agreement between vessels as well as potential vessel angle and vessel size dependences., Results: Very good correlation (r = .88) was found between SBO-based and QSM-based OEF estimates in SSS. Only QSM showed a moderate correlation (r = .61) between corresponding OEF estimates in SSS and SS. For SBO, a trend of increasing OEF estimates was observed as the SS vessel angle relative to the main magnetic field increased. No obvious size dependence could be established for any method. The R2*-based OEF estimates were reasonable (35%-36%), but the observed range was somewhat low., Conclusion: The results indicate that QSM is a promising candidate for assessment of OEF estimates, for example, providing reasonably robust estimates across a wide range of vessel orientations., (© 2022 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Dynamic glucose-enhanced (DGE) magnetic resonance imaging (MRI) has shown potential for tumor imaging using D-glucose as a biodegradable contrast agent. The DGE signal change is small at 3 T (around 1%) and accurate detection is hampered by motion. The intravenous D-glucose injection is associated with transient side effects that can indirectly generate subject movements. In this study, the aim was to study DGE arterial input functions (AIFs) in healthy volunteers at 3 T for different scanning protocols, as a step towards making the glucose chemical exchange saturation transfer (glucoCEST) protocol more robust. Two different infusion durations (1.5 and 4.0 min) and saturation frequency offsets (1.2 and 2.0 ppm) were used. The effect of subject motion on the DGE signal was studied by using motion estimates retrieved from standard retrospective motion correction to create pseudo-DGE maps, where the apparent DGE signal changes were entirely caused by motion. Furthermore, the DGE AIFs were compared with venous blood glucose levels. A significant difference (p = 0.03) between arterial baseline and postinfusion DGE signal was found after D-glucose infusion. The results indicate that the measured DGE AIF signal change depends on both motion and blood glucose concentration change, emphasizing the need for sufficient motion correction in glucoCEST imaging. Finally, we conclude that a longer infusion duration (e.g. 3-4 min) should preferably be used in glucoCEST experiments, because it can minimize the glucose infusion side effects without negatively affecting the DGE signal change., (© 2021 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Purpose: To optimize a whole-brain magnetization transfer saturation (MT sat ) protocol at 7T, focusing on maximizing obtainable MT sat under the constraints of specific absorption rate (SAR) and transmit field inhomogeneity, while avoiding bias and keeping scan time short., Theory and Methods: MT sat is a semi-quantitative metric, obtained by spoiled gradient-echo MRI in the imaging steady-state. Optimization was based on an established 7T dual flip angle protocol, and focused on MT pulse, readout flip angle, repetition time (TR), offset frequency (Δ), and correction of residual effects from transmit field inhomogeneities by separate flip angle mapping., Results: A 100% SAR level was reached at a 180° MT pulse flip angle, using a compact sinc main lobe (4 ms duration) and minimum TR = 26.5 ms. The use of Δ = +2.0 kHz caused no discernible direct saturation, while Δ = -2.0 kHz resulted in 45% higher MT sat in white matter (WM) compared to Δ = +2.0 kHz. A 4° readout flip angle eliminated bias while yielding a good signal-to-noise ratio. Increased TR yielded only a little increase in MT sat , and TR = 26.5 ms (scan time 04:58 min) was thus selected. Post hoc transmit field correction clearly improved homogeneity, especially in WM., Conclusions: The range of MT sat is limited at 7T, and this can partly be overcome by the exploitation of the asymmetry of the macromolecular lineshape through the sign of Δ. To reduce scan time, a compact MT pulse with a sufficiently narrow frequency response should be used. TR and readout flip angle should be kept short/small. Transmit field correction through separate flip angle mapping is required., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

People learn new languages with varying degrees of success but what are the neuroanatomical correlates of the difference in language-learning aptitude? In this study, we set out to investigate how differences in cortical morphology and white matter microstructure correlate with aptitudes for vocabulary learning, phonetic memory, and grammatical inferencing as measured by the first-language neutral LLAMA test battery. We used ultra-high field (7T) magnetic resonance imaging to estimate the cortical thickness and surface area from sub-millimeter resolved image volumes. Further, diffusion kurtosis imaging was used to map diffusion properties related to the tissue microstructure from known language-related white matter tracts. We found a correlation between cortical surface area in the left posterior-inferior precuneus and vocabulary learning aptitude, possibly indicating a greater predisposition for storing word-figure associations. Moreover, we report negative correlations between scores for phonetic memory and axial kurtosis in left arcuate fasciculus as well as mean kurtosis, axial kurtosis, and radial kurtosis of the left superior longitudinal fasciculus III, which are tracts connecting cortical areas important for phonological working memory., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction: Multi-component T 2 mapping using a gradient- and spin-echo (GraSE) acquisition has become standard for myelin water imaging at 3 T. Higher magnetic field strengths promise signal-to-noise ratio benefits but face specific absorption rate limits and shortened T 2 times. This study investigates compartmental T 2 times in vivo and addresses advantages and challenges of multi-component T 2 mapping at 7 T., Methods: We acquired 3D multi-echo GraSE data in seven healthy adults at 7 T, with three subjects also scanned at 3 T. Stimulated echoes arising from B 1 + inhomogeneities were accounted for by the extended phase graph (EPG) algorithm. We used the computed T 2 distributions to determine T 2 times that identify different water pools and assessed signal-to-noise and fit-to-noise characteristics of the signal estimation. We compared short T 2 fractions and T 2 properties of the intermediate water pool at 3 T and 7 T., Results: Flip angle mapping confirmed that EPG accurately determined the larger B 1 + inhomogeneity at 7 T. Multi-component T 2 analysis demonstrated shortened T 2 times at 7 T compared with 3 T. Fit-to-noise and signal-to-noise ratios were improved at 7 T but depended on B 1 + homogeneity. Adjusting the shortest T 2 to 8 ms and the T 2 threshold that separates different water compartments to 20 ms yielded short T 2 fractions at 7 T that conformed to 3 T data. Short T 2 fractions in myelin-rich white matter regions were lower at 7 T than at 3 T, and higher in iron-rich structures., Discussion: Adjusting the T 2 compartment boundaries was required due to the shorter T 2 relaxation times at 7 T. Shorter echo spacing would better sample the fast decaying signal but would increase peripheral nerve stimulation. Multi-channel transmission will improve T 2 measurements at 7 T., Conclusion: We used a multi-echo 3D GraSE sequence to characterize the multi-exponential T 2 decay at 7 T. We adapted T 2 parameters for evaluation of the short T 2 fraction. Obtained 7 T multi-component T 2 maps were in good agreement with 3 T data., (© 2020 John Wiley & Sons, Ltd.)

Multicenter clinical and quantitative magnetic resonance imaging (qMRI) studies require a high degree of reproducibility across different sites and scanner manufacturers, as well as time points. We therefore implemented a multiparameter mapping (MPM) protocol based on vendor's product sequences and demonstrate its repeatability and reproducibility for whole-brain coverage. Within ~20 min, four MPM metrics (magnetization transfer saturation [MT], proton density [PD], longitudinal [R1], and effective transverse [R2*] relaxation rates) were measured using an optimized 1 mm isotropic resolution protocol on six 3 T MRI scanners from two different vendors. The same five healthy participants underwent two scanning sessions, on the same scanner, at each site. MPM metrics were calculated using the hMRI-toolbox. To account for different MT pulses used by each vendor, we linearly scaled the MT values to harmonize them across vendors. To determine longitudinal repeatability and inter-site comparability, the intra-site (i.e., scan-rescan experiment) coefficient of variation (CoV), inter-site CoV, and bias across sites were estimated. For MT, R1, and PD, the intra- and inter-site CoV was between 4 and 10% across sites and scan time points for intracranial gray and white matter. A higher intra-site CoV (16%) was observed in R2* maps. The inter-site bias was below 5% for all parameters. In conclusion, the MPM protocol yielded reliable quantitative maps at high resolution with a short acquisition time. The high reproducibility of MPM metrics across sites and scan time points combined with its tissue microstructure sensitivity facilitates longitudinal multicenter imaging studies targeting microstructural changes, for example, as a quantitative MRI biomarker for interventional clinical trials., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Purpose: To address the systematic bias in whole-brain dual flip angle (DFA) T 1 -mapping at 7T by optimizing the flip angle pair and carefully selecting radiofrequency (RF) pulse shape and duration., Theory and Methods: Spoiled gradient echoes can be used to estimate whole-brain maps of T 1 . This can be accomplished by using only two acquisitions with different flip angles, that is, a DFA-based approach. Although DFA-based T 1 -mapping is seemingly straightforward to implement, it is sensitive to bias caused by incomplete spoiling and incidental magnetization transfer effects. Further bias is introduced by the increased B 0 and B 1 + inhomogeneities at 7T. Experiments were performed to determine the optimal flip angle pair and appropriate RF pulse shape and duration. Obtained T 1 estimates were validated using inversion recovery prepared echo planar imaging and compared to literature values. A multi-echo readout was used to increase signal-to-noise ratio, enabling quantification of R 2 ∗ and susceptibility, χ., Results: Incomplete spoiling was observed above a local flip angle of approximately 20°. An asymmetric gauss-filtered sinc pulse with a constant duration of 700 μs showed a sufficiently flat frequency response profile to avoid incomplete excitation in areas with high B 0 offsets. A pulse duration of 700 μs minimized effects from incidental magnetization transfer., Conclusion: When performing DFA-based T 1 -mapping one should (a) limit the higher flip angle to avoid incomplete spoiling, (b) use a RF pulse shape insensitive to B 0 inhomogeneities and (c) apply a constant RF pulse duration, balanced to minimize incidental magnetization transfer., (© 2020 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a method for retrospective artifact elimination of MRS data. This retrospective method was based on an approach that combines jackknife analyses with the correlation of spectral windows, and therefore termed "JKC.", Methods: Twelve healthy volunteers performed 3 separate measurement protocols using a 3T MR system. One protocol consisted of 2 cerebellar MEGA-PRESS measurements: 1 reference and 1 measurement including head movements. One-third of the artifact-influenced datasets were treated as training data for the implementation the JKC method, and the rest were used for validation., Results: The implemented JKC method correctly characterized most of the validation data. Additionally, after elimination of the detected artifacts, the resulting concentrations were much closer to those computed for the reference datasets. Moreover, when the JKC method was applied to the reference data, the estimated concentrations were not affected, compared with standard averaging., Conclusion: The implemented JKC method can be applied without any extra cost to MRS data, regardless of whether the dataset has been contaminated by artifacts. Furthermore, the results indicate that the JKC method could be used as a quality control of a dataset, or as an indication of whether a shift in voxel placement has occurred during the measurement., (© 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Background: This study determined the pharmacokinetics of the contrast agent gadobutrol in marmosets by quantitative MRI to derive guidelines for neuroimaging protocols., Methods: Local concentrations of gadobutrol were determined from consecutive gradient echo-based mapping of the relaxation rate R1 on a clinical 3T MRI scanner. Half-time of renal elimination was measured after injection of a triple dose of gadobutrol (0.3 mmol/kg) into the saphenous vein. A first-order single-compartment model was fitted to the measured R1 values and verified by blood analysis., Results: Slow injection (1.5 minutes) resulted in an elimination half-time of 26±4 minutes. After bolus injection (15 seconds), elimination was much slower (62±8 minutes) with 45% larger distribution volumes. Importantly, more gadobutrol entered the cerebrospinal fluid., Conclusions: Slow injection and a latency of about 20 minutes are recommended to avoid extravasation. Application of a triple dose of gadobutrol compensates for the fast elimination in healthy marmosets., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The high gray-white matter contrast and spatial resolution provided by T1-weighted magnetic resonance imaging (MRI) has made it a widely used imaging protocol for computational anatomy studies of the brain. While the image intensity in T1-weighted images is predominantly driven by T1, other MRI parameters affect the image contrast, and hence brain morphological measures derived from the data. Because MRI parameters are correlates of different histological properties of brain tissue, this mixed contribution hampers the neurobiological interpretation of morphometry findings, an issue which remains largely ignored in the community. We acquired quantitative maps of the MRI parameters that determine signal intensities in T1-weighted images (R1 (=1/T1), R2 *, and PD) in a large cohort of healthy subjects (n = 120, aged 18-87 years). Synthetic T1-weighted images were calculated from these quantitative maps and used to extract morphometry features-gray matter volume and cortical thickness. We observed significant variations in morphometry measures obtained from synthetic images derived from different subsets of MRI parameters. We also detected a modulation of these variations by age. Our findings highlight the impact of microstructural properties of brain tissue-myelination, iron, and water content-on automated measures of brain morphology and show that microstructural tissue changes might lead to the detection of spurious morphological changes in computational anatomy studies. They motivate a review of previous morphological results obtained from standard anatomical MRI images and highlight the value of quantitative MRI data for the inference of microscopic tissue changes in the healthy and diseased brain. Hum Brain Mapp 37:1801-1815, 2016. © 2016 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc., (© 2016 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.)

Purpose: The longitudinal relaxation rate (R1 ) measured in vivo depends on the local microstructural properties of the tissue, such as macromolecular, iron, and water content. Here, we use whole brain multiparametric in vivo data and a general linear relaxometry model to describe the dependence of R1 on these components. We explore a) the validity of having a single fixed set of model coefficients for the whole brain and b) the stability of the model coefficients in a large cohort., Methods: Maps of magnetization transfer (MT) and effective transverse relaxation rate (R2 *) were used as surrogates for macromolecular and iron content, respectively. Spatial variations in these parameters reflected variations in underlying tissue microstructure. A linear model was applied to the whole brain, including gray/white matter and deep brain structures, to determine the global model coefficients. Synthetic R1 values were then calculated using these coefficients and compared with the measured R1 maps., Results: The model's validity was demonstrated by correspondence between the synthetic and measured R1 values and by high stability of the model coefficients across a large cohort., Conclusion: A single set of global coefficients can be used to relate R1 , MT, and R2 * across the whole brain. Our population study demonstrates the robustness and stability of the model., (© 2014 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc.)

Despite advances in understanding basic organizational principles of the human basal ganglia, accurate in vivo assessment of their anatomical properties is essential to improve early diagnosis in disorders with corticosubcortical pathology and optimize target planning in deep brain stimulation. Main goal of this study was the detailed topological characterization of limbic, associative, and motor subdivisions of the subthalamic nucleus (STN) in relation to corresponding corticosubcortical circuits. To this aim, we used magnetic resonance imaging and investigated independently anatomical connectivity via white matter tracts next to brain tissue properties. On the basis of probabilistic diffusion tractography we identified STN subregions with predominantly motor, associative, and limbic connectivity. We then computed for each of the nonoverlapping STN subregions the covariance between local brain tissue properties and the rest of the brain using high-resolution maps of magnetization transfer (MT) saturation and longitudinal (R1) and transverse relaxation rate (R2*). The demonstrated spatial distribution pattern of covariance between brain tissue properties linked to myelin (R1 and MT) and iron (R2*) content clearly segregates between motor and limbic basal ganglia circuits. We interpret the demonstrated covariance pattern as evidence for shared tissue properties within a functional circuit, which is closely linked to its function. Our findings open new possibilities for investigation of changes in the established covariance pattern aiming at accurate diagnosis of basal ganglia disorders and prediction of treatment outcome., (Copyright © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.)

Objectives: Idiopathic-generalized epilepsy (IGE) is currently considered to be a genetic disease without structural alterations on conventional MRI. However, voxel-based morphometry has shown abnormalities in IGE. Another method to analyze the microstructure of the brain is diffusion-tensor imaging (DTI). We sought to clarify which structural alterations are present in IGE and the most frequent subsyndrome juvenile myoclonic epilepsy (JME)., Experimental Design: We studied 25 patients (13 IGE and 12 JME) and 44 healthy controls with DTI. Fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivity (AD/RD) were calculated and group differences were analyzed using tract-based spatial statistics (TBSS). Additionally we performed a target-based classification of TBSS results based on the Freesurfer cortical regions. PRINCIPLE OBSERVATIONS: TBSS showed widespread FA reductions as well as MD and RD increases in patients compared to controls. Affected areas were corpus callosum, corticospinal tract, superior and inferior longitudinal fasciculus and supplementary motor regions. No significant differences were found between JME and IGE subgroups. The target-based classification confirmed a particular involvement of the superior frontal gyrus (mesiofrontal area) in IGE/ME., Conclusions: IGE and JME patients showed clear microstructural alterations in several large white matter tracts. Similar findings have been reported in rodent models of IGE. Previous, region-of-interest-based DTI studies may have under-estimated the spatial extent of structural loss associated with generalized epilepsy. The comparison of clinically defined JME and IGE groups revealed no significant DTI differences in our cohort.

Background and Objectives: The thalamus exerts a pivotal role in pain processing and cortical excitability control, and migraine is characterized by repeated pain attacks and abnormal cortical habituation to excitatory stimuli. This work aimed at studying the microstructure of the thalamus in migraine patients using an innovative multiparametric approach at high-field magnetic resonance imaging (MRI)., Design: We examined 37 migraineurs (22 without aura, MWoA, and 15 with aura, MWA) as well as 20 healthy controls (HC) in a 3-T MRI equipped with a 32-channel coil. We acquired whole-brain T1 relaxation maps and computed magnetization transfer ratio (MTR), generalized fractional anisotropy, and T2* maps to probe microstructural and connectivity integrity and to assess iron deposition. We also correlated the obtained parametric values with the average monthly frequency of migraine attacks and disease duration., Results: T1 relaxation time was significantly shorter in the thalamus of MWA patients compared with MWoA (P < 0.001) and HC (P ≤ 0.01); in addition, MTR was higher and T2* relaxation time was shorter in MWA than in MWoA patients (P < 0.05, respectively). These data reveal broad microstructural alterations in the thalamus of MWA patients compared with MWoA and HC, suggesting increased iron deposition and myelin content/cellularity. However, MWA and MWoA patients did not show any differences in the thalamic nucleus involved in pain processing in migraine., Conclusions: There are broad microstructural alterations in the thalamus of MWA patients that may underlie abnormal cortical excitability control leading to cortical spreading depression and visual aura., (Copyright © 2013 Wiley Periodicals, Inc.)

X-linked creatine transport (CRTR) deficiency, caused by mutations in the SLC6A8 gene, leads to intellectual disability, speech delay, epilepsy, and autistic behavior in hemizygous males. Additional diagnostic features are depleted brain creatine levels and increased creatine/creatinine ratio (cr/crn) in urine. In heterozygous females the phenotype is highly variable and diagnostic hallmarks might be inconclusive. This survey aims to explore the intrafamilial variability of clinical and brain proton Magnetic Resonance Spectroscopy (MRS) findings in males and females with CRTR deficiency. X-chromosome exome sequencing identified a novel missense mutation in the SLC6A8 gene (p.G351R) in a large family with X-linked intellectual disability. Detailed clinical investigations including neuropsychological assessment, measurement of in vivo brain creatine concentrations using quantitative MRS, and analyses of creatine metabolites in urine were performed in five clinically affected family members including three heterozygous females and one hemizygous male confirming the diagnosis of CRTR deficiency. The severe phenotype of the hemizygous male was accompanied by most distinct aberrations of brain creatine concentrations (-83% in gray and -79% in white matter of age-matched normal controls) and urinary creatine/creatinine ratio. In contrast, the heterozygous females showed varying albeit generally milder phenotypes with less severe brain creatine (-50% to -33% in gray and -45% to none in white matter) and biochemical urine abnormalities. An intrafamilial correlation between female phenotype, brain creatine depletion, and urinary creatine abnormalities was observed. The combination of powerful new technologies like exome-next-generation sequencing with thorough systematic evaluation of patients will further expand the clinical spectrum of neurometabolic diseases.

Voxel-based morphometry (VBM) shows a differentiated pattern in patients with atypical Parkinson syndrome but so far has had little impact in individual cases. It is desirable to translate VBM findings into clinical practice and individual classification. To this end, we examined whether a support vector machine (SVM) can provide useful accuracies for the differential diagnosis. We acquired a volumetric 3D T1-weighted MRI of 21 patients with idiopathic Parkinson syndrome (IPS), 11 multiple systems atrophy (MSA-P) and 10 progressive supranuclear palsy (PSP), and 22 healthy controls. Images were segmented, normalized, and compared at group level with SPM8 in a classical VBM design. Next, a SVM analysis was performed on an individual basis with leave-one-out cross-validation. VBM showed a strong white matter loss in the mesencephalon of patients with PSP, a putaminal grey matter loss in MSA, and a cerebellar grey matter loss in patients with PSP compared with IPS. The SVM allowed for an individual classification in PSP versus IPS with up to 96.8% accuracy with 90% sensitivity and 100% specificity. In MSA versus IPS, an accuracy of 71.9% was achieved; sensitivity, however, was low with 36.4%. Patients with IPS could not be differentiated from controls. In summary, a voxel-based SVM analysis allows for a reliable classification of individual cases in PSP that can be directly clinically useful. For patients with MSA and IPS, further developments like quantitative MRI are needed., (Copyright © 2011 Wiley-Liss, Inc.)

A novel linear parameterization for the variable flip angle method for longitudinal relaxation time T(1) quantification from spoiled steady state MRI is derived from the half angle tangent transform, τ, of the flip angle. Plotting the signal S at coordinates x=Sτ and y=S/τ, respectively, establishes a line that renders signal amplitude and relaxation term separately as y-intercept and slope. This representation allows for estimation of the respective parameter from the experimental data. A comprehensive analysis of noise propagation is performed. Numerical results for efficient optimization of longitudinal relaxation time and proton density mapping experiments are derived. Appropriate scaling allows for a linear presentation of data that are acquired at different short pulse repetition times, TR << T1 thus increasing flexibility in the data acquisition by removing the limitation of a single pulse repetition time. Signal bias, like due to slice-selective excitation or imperfect spoiling, can be readily identified by systematic deviations from the linear plot. The method is illustrated and validated by 3T experiments on phantoms and human brain., (Copyright © 2011 Wiley-Liss, Inc.)

MRI techniques such as quantitative imaging and parallel transmit require precise knowledge of the radio-frequency transmit field (B(1) (+)). Three published methods were optimized for robust B(1) (+) mapping at 3T in the human brain: three-dimensional (3D) actual flip angle imaging (AFI), 3D echo-planar imaging (EPI), and two-dimensional (2D) stimulated echo acquisition mode (STEAM). We performed a comprehensive comparison of the methods, focusing on artifacts, reproducibility, and accuracy compared to a reference 2D double angle method. For the 3D AFI method, the addition of flow-compensated gradients for diffusion damping reduced the level of physiological artifacts and improved spoiling of transverse coherences. Correction of susceptibility-induced artifacts alleviated image distortions and improved the accuracy of the 3D EPI imaging method. For the 2D STEAM method, averaging over multiple acquisitions reduced the impact of physiological noise and a new calibration method enhanced the accuracy of the B(1) (+) maps. After optimization, all methods yielded low noise B(1) (+) maps (below 2 percentage units), of the nominal flip angle value (p.u.) with a systematic bias less than 5 p.u. units. Full brain coverage was obtained in less than 5 min. The 3D AFI method required minimal postprocessing and showed little sensitivity to off-resonance and physiological effects. The 3D EPI method showed the highest level of reproducibility. The 2D STEAM method was the most time-efficient technique., ((c) 2010 Wiley-Liss, Inc.)

Attempts to optimize the magnetization transfer ratio (MTR) obtained from spoiled gradient echo MRI have focused on the properties of the magnetization transfer pulse. In particular, continuous-wave models do not explicitly account for the effects of excitation and relaxation on the MTR. In this work, these were modeled by an approximation of free relaxation between the radiofrequency pulses and of an instantaneous saturation event describing the magnetization transfer pulse. An algebraic approximation of the signal equation can be obtained for short pulse repetition time and small flip angles. This greatly facilitated the mathematical treatment and understanding of the MTR. The influence of inhomogeneous radiofrequency fields could be readily incorporated. The model was verified on the human brain in vivo at 3 T by variation of flip angle and pulse repetition time. The corresponding range in MTR was similar to that observed by a 4-fold increase of magnetization transfer pulse power. Choice of short pulse repetition time and larger flip angles improved the MTR contrast and reduced the influence of radiofrequency inhomogeneity. Optimal contrast is obtained around an MTR of 50%, and noise progression is reduced when a high reference signal is obtained., ((c) 2010 Wiley-Liss, Inc.)

Magnetization transfer effects represent a major source of contrast in multislice turbo spin echo sequences (TSE)/fast spin echo sequences. Generally, low refocusing flip angles have become common in such MRI sequences, especially to mitigate specific absorption rate problems. Since the strength of magnetization transfer effects is related to the radiofrequency power and therefore specific absorption rate applied, magnetization transfer induced signal attenuations are investigated for a variety of TSE sequences with low constant and variable flip angles. Noticeable differences between the sequences have been observed. In particular, fewer signal attenuations are observed for TSE with low flip angles such as hyperecho-TSE and smooth transitions between pseudo steady states-TSE, leading to contrast that is less dependent on the number of slices. It is shown that the strength of the magnetization transfer-induced signal attenuations can be understood and described by a physical framework, which is based on the mean square flip angle of a given TSE sequence., (Copyright (c) 2009 Wiley-Liss, Inc.)

An empirical equation for the magnetization transfer (MT) FLASH signal is derived by analogy to dual-excitation FLASH, introducing a novel semiquantitative parameter for MT, the percentage saturation imposed by one MT pulse during TR. This parameter is obtained by a linear transformation of the inverse signal, using two reference experiments of proton density and T(1) weighting. The influence of sequence parameters on the MT saturation was studied. An 8.5-min protocol for brain imaging at 3 T was based on nonselective sagittal 3D-FLASH at 1.25 mm isotropic resolution using partial acquisition techniques (TR/TE/alpha = 25ms/4.9ms/5 degrees or 11ms/4.9ms/15 degrees for the T(1) reference). A 12.8 ms Gaussian MT pulse was applied 2.2 kHz off-resonance with 540 degrees flip angle. The MT saturation maps showed an excellent contrast in the brain due to clearly separated distributions for white and gray matter and cerebrospinal fluid. Within the limits of the approximation (excitation <15 degrees , TR/T(1) less sign 1) the MT term depends mainly on TR, the energy and offset of the MT pulse, but hardly on excitation and T(1) relaxation. It is inherently compensated for inhomogeneities of receive and transmit RF fields. The MT saturation appeared to be a sensitive parameter to depict MS lesions and alterations of normal-appearing white matter., ((c) 2008 Wiley-Liss, Inc.)

Higher field strengths entail less homogeneous RF fields. This may influence quantitative MRI and MRS. A method for rapidly mapping the RF field in the human head with minimal distortion was developed on the basis of a single-shot stimulated echo acquisition mode (STEAM) sequence. The flip angle of the second RF pulse in the STEAM preparation was set to 60 degrees and 100 degrees instead of 90 degrees , inducing a flip angle-dependent signal change. A quadratic approximation of this trigonometric signal dependence together with a calibration accounting for slice excitation-related bias allowed for directly determining the RF field from the two measurements only. RF maps down to the level of the medulla could be obtained in less than 1 min and registered to anatomical volumes by means of the T(2)-weighted STEAM images. Flip angles between 75% and 125% of the nominal value were measured in line with other methods.

From the half-angle substitution of trigonometric terms in the Ernst equation, rational approximations of the flip angle dependence of the FLASH signal can be derived. Even the rational function of the lowest order was in good agreement with the experiment for flip angles up to 20 degrees . Three-dimensional maps of the signal amplitude and longitudinal relaxation rates in human brain were obtained from eight subjects by dual-angle measurements at 3T (nonselective 3D-FLASH, 7 degrees and 20 degrees flip angle, TR = 30 ms, isotropic resolution of 0.95 mm, each 7:09 min). The corresponding estimates of T1 and signal amplitude are simple algebraic expressions and deviated about 1% from the exact solution. They are ill-conditioned to estimate the local flip angle deviation but can be corrected post hoc by division of squared RF maps obtained by independent measurements. Local deviations from the nominal flip angles strongly affected the relaxation estimates and caused considerable blurring of the T1 histograms., ((c) 2008 Wiley-Liss, Inc.)

Magnetization transfer (MT) by equidistant pulse trains can be described as being analogous to progressive partial saturation, where 'direct' saturation of water is amplified by MT contributions that are dependent on macromolecular content and differential saturation. This concept was applied to study the transition to steady state in the human brain using similar MT-pulses as in imaging. Up to 41 bell-shaped MT-pulses of 12 ms duration were applied at frequency offsets between 0.5 and 15 kHz with flip angles between 1080 and 1440 degrees . Central white and parietal gray matter was studied in human subjects using STEAM for localized read-out (TE = 30 ms, TM = 13.7 ms). The apparent degree of saturation, delta(app), and the longitudinal relaxation of the water pool during the pulse repetition period (PR) were fitted to the transient behavior after signal correction for cerebro-spinal fluid. PR was varied between 15 and 100 ms to assess the PR-dependence of the fitted parameters. The MT-term in delta(app) exceeded the direct saturation and attained its maximum at PR > or = 100 ms. The macromolecular pool was only partially saturated by a single MT-pulse. The offset may be increased to 2.5 kHz to reduce direct saturation without sacrificing MT in white matter. The estimated relaxation rates (1.04 +/- 0.11 s(-1) in WM; 0.76 +/- 0.13 s(-1) in GM) were faster than are commonly observed at 1.5 T. The apparent saturation is a measure for MT that is not confounded by relaxation. To maximize MT in brain tissue, MT-pulses should be applied at PR = 100 ms or longer. At shorter PR, a larger steady state saturation is obtained at the cost of increased contributions from direct saturation. Since this accelerates the convergence, PR should be decreased to reach the steady state within a specified time. A faster transition can always be achieved at a reduced frequency offset via increased direct saturation., (Copyright 2004 John Wiley & Sons, Ltd.)

In vivo longitudinal relaxation times of N-acetyl compounds (NA), choline-containing substances (Cho), creatine (Cr), myo-inositol (mI), and tissue water were measured at 1.5 and 3 T using a point-resolved spectroscopy (PRESS) sequence with short echo time (TE). T(1) values were determined in six different brain regions: the occipital gray matter (GM), occipital white matter (WM), motor cortex, frontoparietal WM, thalamus, and cerebellum. The T(1) relaxation times of water protons were 26-38% longer at 3 T than at 1.5 T. Significantly longer metabolite T(1) values at 3 T (11-36%) were found for NA, Cho, and Cr in the motor cortex, frontoparietal WM, and thalamus. The amounts of GM, WM, and cerebrospinal fluid (CSF) within the voxel were determined by segmentation of a 3D image data set. No influence of tissue composition on metabolite T(1) values was found, while the longitudinal relaxation times of water protons were strongly correlated with the relative GM content., (Copyright 2003 Wiley-Liss, Inc.)

The effect of edema on metabolic changes in contrast-enhancing multiple sclerosis lesions was studied by combining quantification of proton MR spectra with segmentation of the volume-of-interest, which was based on biexponential T(2) relaxation. All lesions showed a second component (s(long)) with a longer T(2) (185-450 ms), which was increased compared to healthy controls. Regression analysis indicated that s(long) replaces the short-T(2) component and total creatine. Since the water content was close to 100%, s(long) was used to correct for an increase in extracellular space. This compensated for the apparent loss of creatine and rendered cholines markedly increased, as observed in animals with experimental allergic encephalomyelitis. Total N-acetyl aspartate (NAA) concentration was inversely correlated with s(long) and between 34-70% of its average reduction was assigned to edema. Thus, NAA loss exceeded cellular loss. Assessment of varying degrees of edema may be especially beneficial for quantitative longitudinal studies.

A postprocessing method to restore motion-related signal loss and line-shape deterioration in single-volume proton MR spectroscopy (MRS) is presented. Each acquisition is corrected by its phase offset and frequency shift, extracted from the residual water signal prior to averaging. Requirements are good gradient selection and selective suppression of CSF in residual water. Stimulated echo acquisition mode (STEAM) spectra (TE = 30 ms) were analyzed using the LCModel program to study gains in metabolite signal and spectral quality in five brain regions. Increases of total N-acetyl-aspartate concentrations of up to 5% were observed. The method may be beneficial for clinical examinations of less compliant subjects and for dynamic spectroscopy.

The aim of this work was to study and correct the influence of varying coil load and local B(1) field in single volume MR spectroscopy. A simple, precise, and user-independent way to adjust the transmitter gain has been developed and validated. It is based on a fit of the localized signal to flip angle variation around 90 degrees. This method proved to be robust against B(1) gradients and suitable for in vivo applications. Local B(1) correction was combined with an external reference and decomposition of the volume into CSF and tissue to obtain a comprehensive absolute quantification of tissue water content and metabolite concentrations in human brain. STEAM localized spectra of parietal and insular gray matter and subparietal white matter (n = 11, TE = 30 ms) were analyzed using a linear combination of model spectra (LCModel). Coefficients of variation (CV) between 1.5% and 4% were obtained for the tissue water content (1-2% in a single subject). The CVs of major metabolite concentrations (4-21%) were dominated by the errors of the spectral analysis. The largest B(1) variation in the in vivo experiments (range 30%) was due to changes in coil load. Differences in regional sensitivity due to B(1) inhomogeneity (parietal: 8% and 9%; insular: 16%) were found to be the second largest source of variation. Correction for local B(1) improved standard deviations and intra-subject reproducibility. On average, sensitivity was 9% less in insular than in parietal gray matter. If ignored, significant differences were introduced for water and N-acetyl-aspartate or were obscured for creatine and cholines. Hence, local sensitivity correction proved to be necessary for regional comparison of absolute metabolite concentrations., (Copyright 2000 John Wiley & Sons, Ltd.)

Localized short echo time magnetic resonance (MR) spectra were obtained from patients with multiple sclerosis of relapsing-remitting or secondary chronic-progressive course and from healthy controls. Automated analysis using model spectra, sensitivity correction, and subtraction of partial ventricular volume yielded tissue concentrations of metabolites that were in line with findings of previous studies. Additional findings were increased creatine in chronic lesions and increased myo-inositol in normal-appearing white matter. Regression analysis was performed to reveal concomitant changes of metabolite concentrations. Differences in the correlations between cholines and myo-inositol suggest increased expression of myo-inositol in chronic lesions or of cholines in active, contrast-enhanced lesions. A correlation between N-acetyl-aspartate and creatine, which is probably due to extracellular edema, was observed in active but not in chronic lesions. Creatine and cholines correlated in chronic lesions, which may be the result of gliosis. The consequences of these findings for the interpretation of absolute concentrations and creatine ratios are discussed.

To assess putative magnetization transfer effects on the proton resonances of cerebral metabolites in human brain, we performed quantitative proton magnetic resonance spectroscopy (2.0 T, STEAM, TR/TE/TM = 6000/40/10 ms, LCModel data evaluation) of white matter (7.68 mL, 10 healthy young subjects) in the absence and presence of fast repetitive off-resonance irradiation (2.1 kHz from the water resonance) using a train of 100 Gaussian-shaped RF pulses (12.8 ms duration, 120 Hz nominal bandwidth, 40 ms repetition period, 1080 degrees nominal flip angle). A comparison of pertinent metabolite concentrations revealed a magnetization transfer attenuation factor of the methyl and methylene resonances of creatine and phosphocreatine of 0.87 +/- 0.05 (p < 0.01). No attenuation was observed for the resonances of N-acetylaspartate and N-acetylaspartylglutamate, glutamate and glutamine, choline-containing compounds, and myo-inositol. The finding for total creatine is in excellent agreement with data reported for rat brain. The results are consistent with the hypothesis of a chemical exchange of mobile creatine or phosphocreatine molecules with a small immobilized or 'bound' pool., (Copyright 1999 John Wiley & Sons, Ltd.)

Metabolic alterations in bovine brain homogenate were examined as a function of post mortem interval (PMI) using high-resolution proton NMR spectroscopy. In particular, while lactate, glutamate, glutamine, creatine and inositols as well as the total concentration of trimethyl-ammonium compounds remained constant, prominent changes due to the hydrolysis of N-acetylaspartate to acetate and aspartate as well as the decomposition of glycerophosphocholine into free choline and glycerol correlated linearly with the duration of PMI (3-195 h). The spectroscopic identification of the latter process was confirmed by proton NMR studies of model solutions as well as of extracts of mammalian brain showing high levels of free glycerol. Since the methylene resonances of glycerol overlap with the proton resonances of myo-inositol, care should be taken in the interpretation of both in vitro and in vivo brain spectra.

Scyllo-inositol has been identified in proton NMR spectra of mammalian brain in vitro and in vivo. In contrast to myo-inositol this isomer comprises six equivalent CH protons that yield a singlet resonance at a chemical shift of 3.35 ppm. 1-D and 2-D J-resolved proton NMR studies (7.0 T) of perchloric acid extracts of brain tissues revealed different amounts of scyllo-inositol in man, sheep, cow and rat. Absolute quantification of localized short-echo time proton NMR spectra (2.0 T) of human brain in vivo resulted in scyllo-inositol concentrations of 0.35 +/- 0.06 mM for white matter (n = 25), 0.43 +/- 0.11 mM for grey matter (n = 23) and 0.57 +/- 0.14 mM for cerebellum (n = 10). Evidence for a tight metabolic link to myo-inositol was supported by a simultaneous variation of myo- and scyllo-inositol in patients with various brain diseases.