Electronic reference for absolute quantification of brain metabolites by 1H-MRS on clinical whole-body imaging.

BACKGROUND AND PURPOSE: The electronic reference to access in vivo concentrations (ERETIC) method is a promising technique for absolute concentration quantification by brain proton magnetic resonance spectroscopy ((1)H-MRS). However, in its usual form, the technique cannot be implemented in most clinical MR scanners. For this reason, we propose a new strategy for transmitting the ERETIC signal before localized spectroscopy acquisition, thereby allowing its use in clinical MR scanners. METHODS: ERETIC signal acquisition, using a dedicated sequence, was carried out immediately before the MR sequence. This approach was evaluated on phantoms of known metabolite concentrations and in 10 healthy volunteers. The results were then compared with those obtained using the water signal as reference. RESULTS: Measurements in vitro showed that the standard deviations measured by the ERETIC method were similar to those using the water-signal reference method. Also, values for metabolite concentrations in vivo were in good agreement with those found in the literature for normal white matter in human brains. Concentrations obtained by ERETIC showed good linear correlation compared with the values obtained by the water-signal reference method. CONCLUSION: Our preliminary study shows that the ERETIC method appears to be a reliable technique that can overcome most of the drawbacks observed with other absolute quantification methods. However, further studies involving larger patient groups are needed to confirm these findings.

Calcium and spermine interaction with phospholipid bilayers: a 15N NMR study.

The binding of Ca2+ to membrane models composed of diplamitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine (DPPE) 15N-labeled in the polar head group was investigated at pH 8.5 and pH 9.4 by 15N-NMR spectroscopy. Both phospholipids exhibit a decrease in the chemical shift anisotropy, indicating changes of the order parameter of the C-N bond and decrease in half-height width. Binding of Ca2+ induces a chemical shift change for the DPPE signal which indicates a decrease in the pKa of the amino group. The binding of spermine was also investigated for mixed phase (DPPC/DPPE) at pH 8 and pH 9.4; a decrease in the DPPE pKa was also noted. The signals of both phospholipids are broadened and the line shapes are more complex because of the lower mobility and the higher steric bulk of this molecule. The results show the value of 15N-NMR in the study of mixed liposomes and indicate that the deprotonation of membrane surface could constitute a necessary step for fusion processes.

Quantitative magnetic resonance and isotopic imaging: early evaluation of radiation injury to the brain.

PURPOSE: Using magnetic resonance (MR) and isotopic imaging to investigate the cerebral alterations after highdose single-fraction irradiation on a pig model. We assessed the nuclear magnetic resonance (NMR) relaxation times as early markers of radiation injury to the healthy brain. METHODS AND MATERIALS: A total of 17 animals was studied; 15 irradiated and 2 unirradiated controls. Pigs were irradiated with a 12 MeV electron beam at a rate of 2 Gy/min. Ten animals received 40 Gy at the 90% isodose, five animals received 60 Gy, and two animals were unirradiated. The follow-up intervals ranged from 2 days to 6 months. T1-weighted scans, T2-weighted scans, and scintigrams were performed on all animals to study neurological abnormalities, cerebral blood flow, and blood-brain barrier (BBB) integrity. T1 and T2 relaxation times were measured in selected regions of interest (ROIs) within the irradiated and contralateral hemispheres. A ratio T1 after irradiation/T1 before irradiation, and a ratio T2 after irradiation/T2 before irradiation, were calculated, pooled for each dose group, and followed as a function of time after irradiation. RESULTS: Scintigraphy visualized the brain perfusion defect and BBB disruption in all irradiated brains. The ratio T2 after irradiation/T2 before irradiation was proportional to the effective dose received. The T2 ratio kinetics could be analyzed in three phases:an immediate and transient phase, two long-lasting phases, which preceded compression of the irradiated lateral ventricle, and edema and necrosis at later stages of radiation injury, respectively. The magnetic resonance imaging (MRI) observations correlated well with histological analysis. CONCLUSION: The results show that quantitative imaging is a sensitive in vivo method for early detection of cerebral radiation injury. The reliability and dose dependence of T2 relaxation time may offer new opportunities to detect and understand brain pathophysiology after high-dose single-fraction irradiation.

T2 relaxation time as a marker of brain myelination: experimental MR study in two neonatal animal models.

The progress of myelination in the brain was evaluated by visualization of grey/white matter differentiation on magnetic resonance (MR) images and quantitative analysis of MR data. In vivo quantitative MR imaging was used to monitor the T2 transverse relaxation time changes associated with cerebral development and myelination. The progress of myelination was evaluated using two neonatal animal models, the monkey and the dog, known to mature at very different rates. Three beagles were studied from birth to 4 months of age and nine baboons from 1 to 30 months of age. The T2 values in the frontal, parietal and occipital white matter were calculated and the changes in these values with age were followed. Brain maturation in both species was found to correspond to decreasing T2 values in both grey and white matter. This decrease was observed both in the dog brain and, despite slower maturation, in the baboon brain, and appeared to fit with the myelination process in these models. Exploiting the physicochemical parameters of water in tissues via T2 determination is a convenient and reliable strategy for the documentation of brain development in both experimental approaches and clinical situations.

Effects of neonatal focal cerebral hypoxia-ischemia on sleep-waking pattern, ECoG power spectra and locomotor activity in the adult rat.

The aim of this study was to determine the influence of neonatal focal cerebral hypoxia-ischemia (HI) on sleep-waking pattern, electrocorticogram (ECoG) power spectra and locomotor activity (LA) in adult Wistar rats. Seven-day old pups were subjected to permanent unilateral ligation of the common carotid artery and transient hypoxia (8% O2). At 10 weeks of age, the extent of brain damages was evaluated by magnetic resonance imaging (MRI) and homogenous injured animals were selected before chronic implantation of radiotelemetry device. Using a single ECoG recording channel method, waking (W), paradoxical sleep (PS) and slow wave sleep (SWS) were continuously recorded for 72 h and they were semi-automatically analyzed off-line. We observed that neonatal HI triggers a cascade of events leading, in adult rats, to brain dysfunction characterized by an increase in SWS (55.0 vs. 40.2% in sham-operated rats, p<0.05) and a marked decrease in W phases duration (43.4 vs. 51.5%, p<0.05) while PS was almost suppressed in HI rats (1.6 vs. 8.3%, p<0.05). In addition, power spectral analysis of ECoG revealed significant (p<0.05) alteration in PS power density with a shift of the dominant frequency peak (5.0 to 7.5 Hz for HI and sham-operated rats, respectively). During the light period, we found that HI induced a pronounced reduction of LA (-30%, p<0.05). These results indicate that Wistar rats exposed to a neonatal unilateral cerebral HI present significant ECoG activity, sleep-waking pattern and behavioral disturbances when adults. However, it remains to establish whether such alterations can be prevented by neuroprotective agents.

Potential of T2 relaxation time measurements for early detection of radiation injury to the brain: experimental study in pigs.

PURPOSE: To investigate the MR T2 relaxation time and histologic changes after a single-fraction 25-Gy dose of radiation to the brain of pigs. METHODS: The right hemisphere of 10 Meishan pigs was irradiated with a single dose of 25 GY at the 90% isodose, using a 12-MeV electron beam. T2 relaxation time was measured within three regions of interest in the brain: those that had received 90%, 70%, and 40% of the total dose, respectively. T2 kinetics over time was compared with histologic studies. RESULTS: Brain T2 values were noted to increase within the irradiated areas. T2 kinetics were analyzed in three phases: an immediate transient phase and two long-lasting phases. These two long-lasting phases were correlated with the detection of ventricular compression and necrosis, respectively. The T2 increase within the 90% region of interest was 19%, 22%, and 26% for phases I, II, and III, respectively. T2 measurements within other regions of interest were not significant. CONCLUSION: Although our results suggest a dose threshold for T2 variations, brain T2 values increased after irradiation at a level at which disease could not be seen on conventional MR images. This illustrates the value of using conventional MR imaging in a quantitative manner to assess molecular tissue abnormalities at earlier stages of developing diseases.

Experimental MR study of cerebral radiation injury: quantitative T2 changes over time and histopathologic correlation.

PURPOSE: To use the pig brain as a large-animal model to examine the effects of high-dose single-fraction irradiation on MR images, T2 relaxation time, and histologic integrity. METHODS: A total of 24 Meishan pigs were studied: 20 irradiated animals and 4 unirradiated controls. A high dose was delivered to the right hemisphere of the animals, using a 12-MeV electron beam. Ten animals received 40 Gy at the 90% isodose, and 10 animals received 60 Gy. Quantitative measurement of T2 relaxation time was compared with qualitative analysis of T2-weighted images and histologic studies. RESULTS: Quantitative analysis revealed a reproducible increase of the T2 parameter within the irradiated areas. The T2 kinetic could be analyzed in two phases, which appeared before the visualization of ventricle compression, necrosis, and edema. The first is characterized by vascular inflammation and the latter by radiation necrosis and edema. Both are dose dependent. CONCLUSION: These results underline the ability of quantitative MR for early diagnosis of brain radiation lesions in vivo.

T1 mapping from spin echo and stimulated echoes.

We present an imaging method to obtain a map of the spin-lattice relaxation time. Images were acquired with the same spatial resolution and in the same time as for a regular spin-echo acquisition. The sequence was based on the simultaneous acquisition of a spin echo and several stimulated echoes with the same intensity except for T1 weighting which increases with the interval between the excitation pulse and the readout pulse. T1 values obtained on phantoms were compared to those from the inversion-recovery method and show the accuracy (2%) and the precision (5%) of the method. T1 images of the brain of a healthy volunteer are presented and demonstrate the ability of the method to obtain T1 mapping in vivo in 12 min and without susceptibility artifacts. In vivo and in vitro results were compared to those obtained by a TOMROP sequence in the same acquisition time.

Correction of intensity nonuniformity in spin-echo T(1)-weighted images.

This paper presents a method to correct intensity nonuniformity in spin-echo T(1)-weighted images and particularly the inhomogeneities due to RF transmission imperfections which have tissue-dependent effects through the T(1) relaxation times. This method is based on the use of a uniform phantom, first for classic normalization by division by the phantom images, and second for T(1)-correction using the RF transmitted cartography. We present experimental results from a bi-phasic (oil/water) phantom and from a salmon with a 0.2 T imager. The results demonstrate the efficiency of the method in the two cases and its ability to cope with partial volume effect.

Radiofrequency map of an NMR coil by imaging.

We propose a new imaging method to obtain a map of the radiofrequency (RF) field amplitude over a sample. The sequence contains three RF pulses (alpha, 2 alpha, and alpha) and produces two images by a classical spin echo and a stimulated echo. A third image is computed and gives the distribution of the flip angle alpha, and so the RF amplitude, over the sample. The accuracy of the flip angle determination is verified on an homogeneous sample and results show a good correlation between experimental and theoretical flip angles in the range of 50 degrees to 130 degrees. Experiments with a surface coil and a resonator show the method is available in an inhomogeneous RF field. Images obtained on the calf of a volunteer confirms the independence of the computed RF distribution from proton density, T1, or T2 contrast.

Superparamagnetic iron oxide nanoparticles as a liver MRI contrast agent: contribution of microencapsulation to improved biodistribution.

We have developed a new method of synthetizing superparamagnetic iron oxide nanoparticles, consisting in the modifications of Molday's method, which ensures high relaxivity (2.4 10(5) s-1.M-1.L), good chemical stability, singular biodistribution and a considerable safety margin. The ED (Efficace Dose) to LD50 ratio is 1/2400 instead of 1/50 for Gd-DTPA. In order to develop a magnetite-delivery system to the liver we have incorporated the nanoparticles into biodegradable synthetic microcapsules. Encapsulated 59Fe oxide nanoparticles are injected into rats; in these conditions the sequestration is 9-fold greater in liver and 6 and 5 times lower in blood and carcase, respectively. This modification of the biodistribution enables the use of magnetite containing microcapsules at only 0.3 mg/kg iron to obtain an improved contrast in liver.

Quantitative MR renography using a calibrated internal signal (ERETIC).

To measure MR renograms, cortical and medullary kidney signal intensity evolution is followed after contrast agent injection. To obtain an accurate quantitative signal measurement, the use of a reference signal is necessary to correct the potential MRI system variations in time. The ERETIC method (Electronic Reference To access In vivo Concentrations) provides an electronic reference signal. It is synthesized as an amplitude modulated RF pulse applied during the acquisition. The ERETIC method was as precise as the external tube reference method but presents major advantages like its free adjustability (shape, location and magnitude) to the characteristics of the organ studied as well as its not taking room inside the magnet. Even though ERETIC showed a very good intrinsic stability, systems' variations still affect its signal in the same way as real NMR signals are affected. This method can be easily implemented on any imaging system with two RF channels.

Acquisition of spin echo and stimulated echo by a single sequence: application to MRI of diffusion.

A new method is described to measure the restricted diffusion coefficient with magnetic resonance imaging. The two images necessary to calculate the diffusion image are obtained with a simultaneous acquisition of a spin-echo and a stimulated echo, and so, in half the time needed by usual spin-echo or stimulated echo method. A different diffusion contrast is created on each echo. A map of an estimate of the diffusion coefficient and an estimation of T1 value are obtained with only one experiment. The accuracy of the method has been evaluated on phantom and results are in agreement with values found in previous papers and with measurements performed with a usual spin-echo method. Furthermore, in vivo measurements have shown that this method can be used without electrocardiogram triggering.

MR assessment of the brain maturation during the perinatal period: quantitative T2 MR study in premature newborns.

The purpose of our study is to trace in vivo and during the perinatal period, the brain maturation process with exhaustive measures of the T2 relaxation time values. We also compared regional myelination progress with variations of the relaxation time values and of brain signal. T2 relaxation times were measured in 7 healthy premature newborns at the post-conceptional age of 37 weeks, using a Carr-Purcell-Meiboom-Gill sequence (echo time 60 to 150 ms), on a 2.35 Tesla Spectro-Imaging MR system. A total of 62 measures were defined for each subject within the brain stem, the basal ganglia and the hemispheric gray and white matter. The mean and standard deviation of the T2 values were calculated for each location. Regional T2 values changes and brain signal variations were studied. In comparison to the adult ones, the T2 relaxation time values of both gray and white matter were highly prolonged and a reversed ratio between gray and white matter was found. The maturational phenomena might be regionally correlated with a T2 value shortening. Significant T2 variations in the brainstem (p < 0.02), the mesencephalon (p < 0.05), the thalami (p < 0.01), the lentiform nuclei (p < 0.01) and the caudate nuclei (p < 0.02) were observed at an earlier time than they were visible on T2-weighted images. In the cerebral hemispheres, T2 values increased from the occipital white matter to parietal, temporal and frontal white matter (p < 0.05) and in the frontal and occipital areas from periventricular to subcortical white matter (p < 0.01). Maturational progress was earlier and better displayed with T2 measurements and T2 mapping. During the perinatal period, the measurements and analysis of T2 values revealed brain regional differences not discernible with T2-weighted images. It might be a more sensitive indicator for assessment of brain maturation.

[Nuclear magnetic resonance spectroscopy: methodology and applications to the study of asphyxia neonatorum]. / La spectroscopie par résonance magnétique nucléaire: méthodologie et applications à l'étude de l'asphyxie périnatale.

Cerebral metabolism has been extensively studied by magnetic resonance spectroscopy (MRS). MRS allows the study of neonates brain maturation as well as the onset and the evolution of brain injury. The use of phosphorous spectroscopy allows the quantification of phosphorylated metabolites. Thus, the measurement of the relative concentrations of creatine-phosphate and inorganic-phosphate is a prognostic factor of the outcome of a neonate after birth asphyxia. Absolute concentrations have more recently been studied and seem to be more significant. Proton MRS gives access to brain metabolites such as choline, lactate, N-acetyl aspartate and taurine. Its use is more recent than the phosphorous spectroscopy but first results already show its potential in neonatology.

Parasagittal magnetic resonance imaging of the lateral pterygoid muscle: a preliminary study.

Ten anatomic territories, including both lateral pterygoid muscle and temporomandibular joint heads, were explored with magnetic resonance imaging in subjects with no dysfunctional disorders. The sequence used was one of inversion-recovery, supplemented with image contrast reversal for better visualization. The muscles were observed in the resting position and in dynamic relation. Slice plane definition provided information on the anatomic variations of the superior head and on the muscle-articular junction, in particular on the fascicular aspect of the superior lateral pterygoid muscle and on the differentiation between condyle insertions under effort. The choice of technique and the results are discussed. Avenues are opened for the exploration of muscles utilizing magnetic resonance imaging.

Twenty-day cerebral and umbilical Doppler monitoring on a growth retarded and hypoxic fetus.

In one growth retarded and hypoxic fetus, the cerebral and umbilical hemodynamic changes were assessed (by Doppler), daily over 20 days. The fetal brain was investigated by magnetic resonance imaging (MRI) close to the delivery, and because the fetus died at delivery we performed an anatomical study of the fetal brain. The evolution of the fetal hemodynamics (day by day) was interpreted according to the MRI findings and the clinical findings. During the period of observation (under sustained hypoxia) the fetal deterioration was characterized by: (a) the progressive development of the oligohydramnios (190d), (b) the disappearance of the vascular reactivity (eight successive cerebral resistance index (RI) constant at 194d), (c) the occurrence of fetal heart rate decelerations (199d), and finally (d) the increase of the cerebral vascular resistances with reduction of the brain perfusion (204d). The anatomical study of the brain showed a periventricular congestion however the histology revealed hypoxic lesions like gliosis and a marked vasodilation of the anterior and middle cerebral arteries. Finally in addition to single Doppler measurements performed 1 week before delivery (for prediction of fetal outcome), one can suggest to use the 'loss of fluctuation of the cerebral RI' to identify the beginning of the period of very high risk for the fetus. Such hypothesis may have to be confirmed on a larger number of pathological pregnancies.

Brain damage and hypoxia in an ovine fetal chronic cocaine model.

OBJECTIVE: To assess the development of brain damage in an ovine fetal chronic cocaine model. To evaluate the effect of isolated hypoxic tests on this model and to correlate hemodynamic findings (brain-sparing effect) following fetal hypoxia and the occurrence of brain damage. STUDY DESIGN: Fifteen ewes were divided into a control group (n=7) and a cocaine treated group (n=8). From day 65 to day 134 the cocaine treated animals received a daily (5 days per week) intramuscular injection (2 mg/kg cocaine) and the control animals a placebo injection (2 ml of isotonic solution). Both groups underwent hypoxic tests (cord compression (3 min) and aortic compression (1 min)) at 90 and 134 days. In addition, anesthesia for magnetic resonance imaging (MRI) examination was carried out at 125 days. Fetal blood samples were collected during both series of hypoxic tests and the cerebral and umbilical flows were monitored by Doppler. Samples from 25 brains (control n = 10; cocaine n= 15) were processed for light and electron microscopic examination. Quantification of brain damage was done on semithin sections from six areas of cortex and germinal matrix on each fetus. RESULTS: Similar forms of brain damage (selective neuronal loss limited to the parasaggital cortex, striatum, hippocampus and Purkinje cells) was present in both groups but lesions were more frequent in the cocaine treated group as shown by quantitative analysis for the proportion of abnormal capillaries (65% vs. 35%), capillary edema (61% vs. 34%) and abnormal neurons showing delayed neuronal degeneration (DND) (66% vs. 36%) in the cocaine and control group respectively. There was no significant difference in immunoreactivity for glial fibrillary acidic protein (GFAP) but it was more marked in the cerebellum of cocaine treated animals. Fetal blood samples showed a moderate sustained hypoxia and Doppler findings demonstrated the presence of a brain sparing effect associated with increased uterine and umbilical vascular resistance in the cocaine treated group. Nevertheless, the amplitude of the heart rate increase and cerebral dilatation was significantly lower in the cocaine treated animals. CONCLUSION: This ovine fetal chronic cocaine model showed the presence of brain damage. Cocaine treatment seems to potentiate the effect of the hypoxic tests. Independent of the cause, the brain damage developed in the presence of brain sparing effect, strongly suggesting that this phenomenon is a sign of a pathological fetal condition and no guarantee that it will prevent tissue damage.

Cerebral MRI on fetuses submitted to repeated cocaine administration during the gestation: an ovine model.

The aim of this study was to determine the role of Magnetic Resonance Imaging (MRI) in investigating fetal cerebral lesions induced by long term exposure to cocaine during sheep pregnancy. Cerebral Magnetic Resonance Imaging was performed on two groups of fetuses at 125 days of gestation (normal gestation: 145 days). The control group consisted of eight fetuses of four pregnant ewes. The study group consisted of eight fetuses of four pregnant ewes receiving daily 140 mg/kg injection of cocaine from day 60 until delivery. The following MR sequences were applied: T1-weighted FLASH, and T2-weighted Fast-Spin-Echo. Cerebral images were evaluated semi quantitatively using the following criteria: Heterogenicity, contrast between grey and white matter, contours irregularity, hyposignal, lateral ventricle sizes. The brightness distribution and homogenicity of the images were analysed by means of edge pair distributions using a new computerized method originally designed for ultrasound images analysis developed by Ultrasight inc (USA). (1) Flash T1: Heterogenic areas and irregular contours were more frequent in cocaine exposed fetuses. The contrast between grey and white matter was more important in the cocaine group. Hyposignal was found only in the cocaine group. Enlarged lateral ventricle occurred more frequently in the cocaine group. (2) Spin echo T2: The contrast between grey and white matter was higher and the contours of the brain more irregular in the cocaine group. Heterogenicity and hyposignal were also more frequent in this group but the difference with the control group was not significant. The computerized analysis of the contrast density on the cerebral images showed that 88% of the areas exceeding the reference level concerned the cocaine group, while only 14% of the areas exceeding the reference level concerned the control group. Long term exposure to cocaine induces cerebral tissue modifications, in favor of an advanced maturation and the development of hypoxic lesions. The histology of the brains confirmed in the cocaine group, the existence of hypoxic lesions with gliosis, perivascular edema and hemorrhages, and neuronal death.

[Use of a stimulated echo sequence in the MRI study of the brain and spine]. / Application de la séquence d'écho stimulé dans l'exploration IRM de l'encéphale et du rachis.

We describe in this paper how the STEAM sequence can be an efficient tool to obtain images free of flow artifacts in anatomical situation where the spin echo failed. The simplest way to eliminate flow artifacts is to exploit the dephasing induced by motion in magnetic field gradients and to reduce to zero the signal from moving tissues. This can be achieve by increasing the time elapsed between the spin excitation and the signal observed. Because of T2 relaxation, such an increase results in a signal decrease when the spin echo sequence is used. The STEAM sequence has the unique property that the time elapsed between observation and excitation can be increased without change in T2 value and so allows a good suppression of signals from the moving spins with short TE. Our results demonstrate that, although the stimulated echo intensity is only half that of a spin echo taken at the same read out time, the advantages of STEAM imaging can compensate for this partial loss in signal to noise in some particular clinical situations. The influence of mixing time on contrast has been evaluated using thoracic spine imaging and it has been shown that contrast between spine and CSF can be significantly improved (+ 60%) when TM is increased (from 17 ms to 50 ms). In the same time, the contrast between spine and fat issue decreases (40%). This last effect facilitates the adjustment of contrast window. Suppression of motion artifacts has first been evaluated with thoracic spine imaging, using a whole body coil. Suppression of artifacts was better than that obtained with a flow compensated spin echo sequence, especially in the case of kyphotic patients when a presaturation band was inefficient. In a second step suppression of motion artifacts has been evaluated from posterior fossa examination after injection of a paramagnetic contrast agent. The images obtained with the stimulated echo sequence show a dramatic reduction of signal from blood in the lateral sinus, and therefore an increase of quality by elimination of motion artifacts.