Investigating lipids as a source of chemical exchange-induced MRI frequency shifts.

While magnetic susceptibility is a major contributor to NMR resonance frequency variations in the human brain, a substantial contribution may come from the chemical exchange of protons between water and other molecules. Exchange-induced frequency shifts fe have been measured in tissue and protein solutions, but relatively lipid-rich white matter (WM) has a larger fe than gray matter, suggesting that lipids could contribute. Galactocerebrosides (GC) are a prime candidate as they are abundant in WM and susceptible to exchange. To investigate this, fe was measured in a model of WM lipid membranes in the form of multilamellar vesicles (MLVs), consisting of a 1:2 molar ratio of GC and phospholipids (POPC), and in MLVs with POPC only. Chemical shift imaging with 15% volume fraction of dioxane, an internal reference whose protons are assumed not to undergo chemical exchange, was used to remove susceptibility-induced frequency shifts in an attempt to measure fe in MLVs at several lipid concentrations. Initial analysis of these measurements indicated a necessity to correct for small unexpected variations in dioxane concentration due to its effect on the water frequency shift. To achieve this, the actual dioxane concentration was inferred from spectral analysis and its additional contribution to fe was removed through separate experiments which showed that the water-dioxane frequency shift depended linearly on the dioxane concentration at low concentrations with a proportionality constant of -0.021 ± 0.002 ppb/mM in agreement with published experiments. Contrary to expectations and uncorrected results, for GC + POPC vesicles, the dependence of the corrected fe on GC concentration was insignificant (0.023 ± 0.037 ppb/mM; r2 = 0.085, p > 0.57), whereas for the POPC-only vesicles a small but significant linear increase with POPC concentration was found: 0.044 ± 0.008 ppb/mM (r2 = 0.877, p < 0.01). These findings suggest that the exchange-induced contribution of lipids to frequency contrast in WM may be small. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

The PRESTO technique for fMRI.

In the early days of BOLD fMRI, the acquisition of T(2)(*) weighted data was greatly facilitated by rapid scan techniques such as EPI. The latter, however, was only available on a few MRI systems that were equipped with specialized hardware that allowed rapid switching of the imaging gradients. For this reason, soon after the invention of fMRI, the scan technique PRESTO was developed to make rapid T(2)(*) weighted scanning available on standard clinical scanners. This method combined echo shifting, which allows for echo times longer than the sequence repetition time, with acquisition of multiple k-space lines per excitation. These two concepts were combined in order to achieve a method fast enough for fMRI, while maintaining a sufficiently long echo time for optimal contrast. PRESTO has been primarily used for 3D scanning, which minimized the contribution of large vessels due to inflow effects. Although PRESTO is still being used today, its appeal has lessened somewhat due to increased gradient performance of modern MRI scanners. Compared to 2D EPI, PRESTO may have somewhat reduced temporal stability, which is a disadvantage for fMRI that may not outweigh the advantage of reduced inflow effects provided by 3D scanning. In this overview, the history of the development of the PRESTO is presented, followed by a qualitative comparison with EPI.

Tissue-specific imaging is a robust methodology to differentiate in vivo T1 black holes with advanced multiple sclerosis-induced damage.

BACKGROUND AND PURPOSE: Brains of patients with multiple sclerosis (MS) characteristically have "black holes" (BHs), hypointense lesions on T1-weighted (T1W) spin-echo (SE) images. Although conventional MR imaging can disclose chronic BHs (CBHs), it cannot stage the degree of their pathologic condition. Tissue-specific imaging (TSI), a recently introduced MR imaging technique, allows selective visualization of white matter (WM), gray matter (GM), and CSF on the basis of T1 values of classes of tissue. We investigated the ability of TSI-CSF to separate CBHs with longer T1 values, which likely represent lesions containing higher levels of destruction and unbound water. MATERIALS AND METHODS: Eighteen patients with MS, who had already undergone MR imaging twice (24 months apart) on a 1.5T scanner, underwent a 3T MR imaging examination. Images acquired at 1.5T included sequences of precontrast and postcontrast T1W SE, T2-weighted (T2W) SE, and magnetization transfer (MT). Sequences obtained at 3T included precontrast and postcontrast T1W SE, T2W SE, T1 inversion recovery prepared fast spoiled gradient recalled-echo (IR-FSPGR) and TSI. A BH on the 3T-IR-FSPGR was defined as a CBH if seen as a hypointense, nonenhancing lesion with a corresponding T2 abnormality for at least 24 months. CBHs were separated into 2 groups: those visible as hyperintensities on TSI-CSF (group A), and those not appearing on the TSI-CSF (group B). RESULTS: Mean MT ratios of group-A lesions (0.22 +/- 0.06, 0.13-0.35) were lower (F(1,13) = 60.39; P < .0001) than those of group-B lesions (0.32 +/- 0.03, 0.27-0.36). CONCLUSIONS: Group-A lesions had more advanced tissue damage; thus, TSI is a potentially valuable method for qualitative and objective identification.

Pittfalls of MRI measurement of white matter perfusion based on arterial spin labeling.

Although arterial spin labeling (ASL) MRI has been successfully applied to measure gray matter (GM) perfusion in vivo, accurate detection of white matter (WM) perfusion has proven difficult. Reported literature values are not consistent with each other or with perfusion measured with other modalities. In this work, the cause of these inconsistencies is investigated. The results suggest that WM perfusion values are substantially affected by the limited image resolution and by signal losses caused by the long transit times in WM, which significantly affect the label. From gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) bolus-tracking experiments (N=6), it is estimated that the transit time can be several seconds long in deep WM. Furthermore, simulations show that even at a spatial resolution of 7 microl voxel size, contamination by the GM signals can exceed 40% of the actual WM signal. From 10-min long flow-sensitive alternating inversion recovery ASL (FAIR-ASL) measurements at 3T in normal subjects (N=7), using highly sensitive detectors, it is shown that single-voxel (7 mul) deep WM perfusion values have an signal-to-noise ratio (SNR) less than 1. The poor sensitivity and heterogeneous transit time limit the applicability of ASL for measurement of perfusion in WM.

Real-time shimming to compensate for respiration-induced B0 fluctuations.

In MRI of human brain, the respiratory cycle can induce B0-field fluctuations through motion of the chest and fluctuations in local oxygen concentration. The associated NMR frequency changes can affect the MRI data in various ways and lead to temporal signal fluctuations, and image artifacts such as ghosting and blurring. Since the size of the effect scales with magnetic field strength, artifacts become particularly problematic at fields above 3.0T. Furthermore, the spatial dependence of the B0-field fluctuations complicates their correction. In this work, a new method is presented that allows compensation of field fluctuations by modulating the B0 shims in real time. In this method, a reference scan is acquired to measure the spatial distribution of the B0 effect related to chest motion. During the actual scan, this information is then used, together with chest motion data, to apply compensating B0 shims in real time. The method can be combined with any type of scan without modifications to the pulse sequence. Real-time B0 shimming is demonstrated to substantially improve the phase stability of EPI data and the image quality of multishot gradient-echo (GRE) MRI at 7T.

fMRI study of effort and information processing in a working memory task.

It is unclear how effort translates into brain function. In this study we endeavored to identify the activity in a working memory task that is related to the allocation of mental resources. Such activity, if present, would be a likely candidate to explain how effort works in terms of brain function. Eleven healthy participants performed a Sternberg task with a memory-set of one, three, or five consonants in an fMRI study. Probe stimuli were either one consonant or one digit. We expected digits to be processed automatically and consonants to require working memory. Because the probe type was unpredictable and subjects had to respond as fast as possible, we expected subjects to allocate mental resources on the basis of the memory-set size, not the probe type. Accordingly, we anticipated that activity in regions involved in effort would be a function of the size of the memory-set, but independent of the type of probe. We found that the reaction-time for digits increased in line with our expectation of automatic processing and the reaction time for letters increased in line with our expectation of controlled processing. fMRI revealed that activity in the right ventral-prefrontal cortex changed as a function of effort. The ventral anterior cingulate cortex and hypothalamus showed reduced activity as a function of effort. Activity in regions regarded as pivotal for working memory (among others, the left dorsolateral prefrontal cortex, anterior cingulate cortex) appeared to be predominantly related to information processing and not involved in effort.

Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells.

Magnetic resonance (MR) tracking of magnetically labeled stem and progenitor cells is an emerging technology, leading to an urgent need for magnetic probes that can make cells highly magnetic during their normal expansion in culture. We have developed magnetodendrimers as a versatile class of magnetic tags that can efficiently label mammalian cells, including human neural stem cells (NSCs) and mesenchymal stem cells (MSCs), through a nonspecific membrane adsorption process with subsequent intracellular (non-nuclear) localization in endosomes. The superparamagnetic iron oxide nanocomposites have been optimized to exhibit superior magnetic properties and to induce sufficient MR cell contrast at incubated doses as low as 1 microg iron/ml culture medium. When containing between 9 and 14 pg iron/cell, labeled cells exhibit an ex vivo nuclear magnetic resonance (NMR) relaxation rate (1/T2) as high as 24-39 s-1/mM iron. Labeled cells are unaffected in their viability and proliferating capacity, and labeled human NSCs differentiate normally into neurons. Furthermore, we show here that NSC-derived (and LacZ-transfected), magnetically labeled oligodendroglial progenitors can be readily detected in vivo at least as long as six weeks after transplantation, with an excellent correlation between the obtained MR contrast and staining for beta-galactosidase expression. The availability of magnetodendrimers opens up the possibility of MR tracking of a wide variety of (stem) cell transplants.

The role of the medial wall and its anatomical variations for bimanual antiphase and in-phase movements.

The medial wall of the frontal cortex is thought to play an important role for bimanual coordination. However, there is uncertainty regarding the exact neuroanatomical regions involved. We compared the activation patterns related to bimanual movements using functional magnetic resonance imaging in 12 healthy right-handed subjects, paying special attention to the anatomical variability of the frontal medial wall. The subjects performed unimanual right and left and bimanual antiphase and in-phase flexion and extension movements of the index finger. Activation of the right supplementary motor area (SMA) proper, right and left caudal cingulate motor area (CMA), and right and left premotor cortices was significantly stronger during bimanual antiphase than bimanual in-phase movements, indicating an important function of these areas with bimanual coordination. A frequent anatomical variation is the presence of the paracingulate sulcus (PCS), which might be an anatomical landmark to determine the location of activated areas. Seven subjects had a bilateral, three a unilateral right, and two a unilateral left PCS. Because the area around the PCS is functionally closer coupled to the CMA than to the SMA, activation found in the area around the PCS should be attributed to the CMA. With anatomical variations such as the presence of a PCS or a vertical branch of the cingulate sulcus, normalization and determination of the activation with the help of stereotaxic coordinates can cause an incorrect shift of CMA activation to the SMA. This might explain some of the discrepancies found in previous studies.

High-sensitivity single-shot perfusion-weighted fMRI.

A method is presented for measurement of perfusion changes during brain activation using a single-shot pulsed spin labeling technique. By employing a double-inversion labeling strategy, stationary tissue (background) signal was suppressed while minimally affecting perfusion sensitivity. This allowed omission of the otherwise required reference scan, resulting in twofold-improved temporal resolution. The method was applied to visual and motor cortex activation studies in humans, and compared to standard FAIR-type perfusion labeling techniques. Experiments performed at 1.5T and 3.0T indicate a close to 90% suppression of background signal, at a cost of an 11% and 9%, respectively, reduction in perfusion signal. Combined with the twofold increase in signal averaging, and a reduction in background signal fluctuations, this resulted in a 64% (1.5T, N = 3) and a 128% (3T, N = 4) overall improvement in sensitivity for the detection of activation-related perfusion changes. Magn Reson Med 46:88-94, 2001. Published 2001 Wiley-Liss, Inc.

CaB6: a new semiconducting material for spin electronics.

Ferromagnetism was recently observed at unexpectedly high temperatures in La-doped CaB6. The starting point of all theoretical proposals to explain this observation is a semimetallic electronic structure calculated for CaB6 within the local density approximation. Here we report the results of parameter-free quasiparticle calculations of the single-particle excitation spectrum which show that CaB6 is not a semimetal but a semiconductor with a band gap of 0.8+/-0.1 eV. Magnetism in La(x)Ca1-xB6 occurs just on the metallic side of a Mott transition in the La-induced impurity band.

The variability of serial fMRI data: correlation between a visual and a motor task.

We investigated whether the intersession variability of serial fMRI studies correlates between two activation modalities, i.e. a standardized visual and a standardized motor task. Six volunteers were scanned in at least weekly intervals. The number of pixels activated as well as the activation amplitude varied widely. The maximal difference of the number of pixels activated was 1150%, of the activation amplitude 250%. In three volunteers, the variability was highly correlated between the two tasks. Three other volunteers showed one outlier each. We conclude that the intersession variability is due to global factors affecting the whole brain, but that due to unpredictable outliers, using a standardized task to normalize the data of interest is of limited value.

The relative metabolic demand of inhibition and excitation.

By using the (14C)2-deoxyglucose method, inhibition has been shown to be a metabolically active process at the level of the synapse. This is supported by recent results from magnetic resonance spectroscopy that related the changes in neuroenergetics occurring with functional activation to neurotransmitter cycling. However, inhibitory synapses are less numerous and strategically better located than excitatory synapses, indicating that inhibition may be more efficient, and therefore less energy-consuming, than excitation. Here we test this hypothesis using event-related functional magnetic resonance imaging in volunteers whose motor cortex was inhibited during the no-go condition of a go/no-go task, as demonstrated by transcranial magnetic stimulation. Unlike excitation, inhibition evoked no measurable change in the blood-oxygenation-level-dependent signal in the motor cortex, indicating that inhibition is less metabolically demanding. Therefore, the 'activation' seen in functional imaging studies probably results from excitation rather than inhibition.

Rapid three-dimensional MR imaging method for tracking a bolus of contrast agent through the brain.

A gradient-echo three-dimensional magnetic resonance imaging technique (principles of echo shifting with a train of observations, or PRESTO) is presented for use in tracking a bolus of paramagnetic contrast agent through the brain. The approach combines a segmented echo-planar type of acquisition with echo shifting, which leads to echo times that are longer than the repetition time. Unlike echo-planar imaging, the method maintains image resolution despite drastic T2* changes and frequency shifts.

Brain myo-inositol level is elevated in Ts65Dn mouse and reduced after lithium treatment.

The segmental trisomy Ts65Dn mouse is a novel model of Down syndrome (DS). The purpose of this study was to measure brain levels of myo-inositol (ml), N-acetylaspartate (NAA), and other metabolites in Ts65Dn mice using in vivo 1H magnetic resonance spectroscopy (MRS), and to determine whether lithium (Li) treatment alters brain ml level. The ratio of ml over total creatine (Cr), ml/Cr, was significantly elevated (mean change +38%), while NAA/Cr was significantly decreased (mean change -18%) in Ts65Dn mice (n=5) compared with control mice (n= 7). This is consistent with 1H MRS findings in DS human adults. Brain ml/Cr of the entire sample group (n= 12) was reduced (mean change -15%) following Li treatment, supporting the Li-induced ml depletion hypothesis.

Local and downstream effects of excitotoxic lesions in the rat medial prefrontal cortex on In vivo 1H-MRS signals.

The rat medial prefrontal cortex (mPFC) regulates subcortical dopamine transmission via projections to the striatum and ventral tegmental area. We used in vivo proton magnetic resonance spectroscopy (1H-MRS) at 4.7 T to determine whether excitotoxic lesions of the mPFC result in alterations of N-acetylaspartate (NAA), a marker of neuronal integrity, both locally and downstream in the striatum. Lesioned rats exhibited persistent reductions of NAA and other metabolites within the prefrontal cortex; selective reductions of NAA were seen in the striatum, but not in the parietal cortex. Consistent with earlier reports, lesioned rats exhibited a transient enhancement in amphetamine-induced hyperlocomotion. Prefrontal NAA losses correlated with lesion extent. In the striatum, while there was no change in tissue volume, expression of striatal glutamic acid decarboxylase-67 mRNA was significantly reduced. In vivo NAA levels thus appear sensitive to both local and downstream alterations in neuronal integrity, and may signal meaningful effects at cellular and behavioral levels.

Neurotransplantation of magnetically labeled oligodendrocyte progenitors: magnetic resonance tracking of cell migration and myelination.

Demyelination is a common pathological finding in human neurological diseases and frequently persists as a result of failure of endogenous repair. Transplanted oligodendrocytes and their precursor cells can (re)myelinate axons, raising the possibility of therapeutic intervention. The migratory capacity of transplanted cells is of key importance in determining the extent of (re)myelination and can, at present, be evaluated only by using invasive and irreversible procedures. We have exploited the transferrin receptor as an efficient intracellular delivery device for magnetic nanoparticles, and transplanted tagged oligodendrocyte progenitor cells into the spinal cord of myelin-deficient rats. Cell migration could be easily detected by using three-dimensional magnetic resonance microscopy, with a close correlation between the areas of contrast enhancement and the achieved extent of myelination. The present results demonstrate that magnetic resonance tracking of transplanted oligodendrocyte progenitors is feasible; this technique has the potential to be easily extended to other neurotransplantation studies involving different precursor cell types.

The effect of movement amplitude on activation in functional magnetic resonance imaging studies.

To evaluate the effect of movement amplitude on the "blood oxygen level-dependent effect," the authors studied six normal subjects while they extended their index finger with two different amplitudes. Images were analyzed using SPM96. In five subjects, the signal intensity increase in the primary sensorimotor area was significantly greater with the larger amplitude movement. In other areas of interest (supplementary motor area, premotor cortex, insula, postcentral area, cerebellum), the large-amplitude movement often showed significant activation when the small-amplitude movement did not. The authors conclude that, in studies of the motor system, movement amplitude needs to be controlled.

Increased iron in the dentate nucleus of patients with Friedrich's ataxia.

Friedreich's ataxia (FA) is the most frequently inherited ataxia. To test the hypothesis that iron is increased in the cerebellum of patients with FA, we developed a multigradient echo magnetic resonance sequence for the three-dimensional imaging of brain iron-induced contrast. Relaxation rate (R2*) values in the unaffected globus pallidus were equal in FA patients and controls, although R2* values in the dentate nucleus of patients were significantly higher, which is most likely due to increased iron.

On the feasibility of MRI-guided focused ultrasound for local induction of gene expression.

Gene therapy is a promising approach to the treatment of many forms of disease, including cancer. Of critical concern in its implementation is the ability to control the location, duration, and level of expression of the therapeutic gene. Here, we propose the use of local heat in combination with a heat-sensitive promoter to help accomplish this. Certain members of the family of heat shock protein (hsp) promoters display a regulation that depends strongly on temperature. We present a study of natural hsp70 induction in rat leg by MRI-guided focused ultrasound to investigate the hsp70 promoter as a possible candidate for use in control of gene expression with local heat. A temperature increase of 5-8 degrees C in the focal region for 45 minutes led to a differential expression of the hsp70 mRNA between the focal region and the surrounding tissue ranging from a factor of 3 to 67.

Functional magnetic resonance imaging brain mapping in psychiatry: methodological issues illustrated in a study of working memory in schizophrenia.

Functional magnetic resonance imaging (fMRI) is a potential paradigm shift in psychiatric neuroimaging. The technique provides individual, rather than group-averaged, functional neuroimaging data, but subtle methodological confounds represent unique challenges for psychiatric research. As an exemplar of the unique potential and problems of fMRI, we present a study of 10 inpatients with schizophrenia and 10 controls performing a novel "n back" working memory (WM) task. We emphasize two key design steps: (1) the use of an internal activation standard (i.e., a physiological control region) to address activation validity, and (2) the assessment of signal stability to control for "activation" artifacts arising from unequal signal variance across groups. In the initial analysis, all but one of the patients failed to activate dorsolateral prefrontal cortex (DLPFC) during the working memory task. However, some patients (and one control) also tended to show sparse control region activation in spite of normal motor performance, a result that raises doubts about the validity of the initial analysis and concerns about unequal subject motion. Subjects were then matched for signal variance (voxel stability), producing a subset of six patients and six controls. In this comparison, the internal activation standard (i.e., motor activation) was similar in both groups, and five of six patients, including two whom were neuroleptic-naive, failed to activate DLPFC. In addition, a tendency for overactivation of parietal cortex was seen. These results illustrate some of the promise and pitfalls of fMRI. Although fMRI generates individual brain maps, a specialized survey of the data is necessary to avoid spurious or unreliable findings, related to artifacts such as motion, which are likely to be frequent in psychiatric patients.