Diffusion tensor imaging in multiple sclerosis at different final outcomes.

OBJECTIVES: Methods to evaluate the relative contributions of demyelination vs axonal degeneration over the long-term course of MS are urgently needed. We used magnetic resonance diffusion tensor imaging (DTI) to estimate degrees of demyelination and axonal degeneration in the corpus callosum (CC) in cases of MS with different final outcomes. MATERIALS AND METHODS: We determined DTI measures mean diffusivity (MD), fractional anisotropy (FA), and axial (AD) and radial (RD) diffusivities in the CC of 31 MS patients, of whom 13 presented a secondary progressive course, 11 a non-progressive course, and seven a monophasic course. The study participants were survivors from an incidence cohort of 254 attack-onset MS patients with 50 years of longitudinal follow-up. As reference, we included five healthy individuals without significant morbidity. RESULTS: In patients with secondary progression, compared to all other groups, the corpus callosum showed increased RD and reduced FA, but no change in AD. None of the parameters exhibited differences among non-progressive and monophasic course groups and controls. CONCLUSION: Increased RD was observed in secondary progressive MS, indicating significant myelin loss. Normal RD values observed in the clinically isolated syndrome and non-progressive groups confirm their benign nature. AD was not a characterizing parameter for long-term outcome. Demyelination revealed by increased RD is a distinguishing trait for secondary progression.

Convection-enhanced drug delivery of interleukin-4 Pseudomonas exotoxin (PRX321): increased distribution and magnetic resonance monitoring.

Convection-enhanced drug delivery (CED) enables achieving a drug concentration within brain tissue and brain tumors that is orders of magnitude higher than by systemic administration. Previous phase I/II clinical trials using intratumoral convection of interleukin-4 Pseudomonas exotoxin (PRX321) have demonstrated an acceptable safety and toxicity profile with promising signs of therapeutic activity. The present study was designed to assess the distribution efficiency and toxicity of this PRX321 using magnetic resonance imaging (MRI) and to test whether reformulation with increased viscosity could enhance drug distribution. Convection of low- [0.02% human serum albumin (HSA)] and high-viscosity (3% HSA) infusates mixed with gadolinium-diethylenetriamine pentaacetic acid and PRX321 were compared with low- and high-viscosity infusates without the drug, in normal rat brains. MRI was used for assessment of drug distribution and detection of early and late toxicity. Representative brain samples were subjected to histological examination. Distribution volumes calculated from the magnetic resonance images showed that the average distribution of 0.02% HSA was larger than that of 0.02% HSA with PRX321 by a factor of 1.98 (p < 0.02). CED of 3.0% HSA, with or without PRX321, tripled the volume of distribution compared with 0.02% HSA with PRX321 (p < 0.015). No drug-related toxicity was detected. These results suggest that the impeded convection of the PRX321 infusate used in previous clinical trials can be reversed by increasing infusate viscosity and lead to tripling of the volume of distribution. This effect was not associated with any detectable toxicity. A similar capability to reverse impeded convection was also demonstrated in a CED model using acetic acid. These results will be implemented in an upcoming phase IIb PRX321 CED trial with a high-viscosity infusate.

Line-scan diffusion tensor imaging of the posttraumatic brain stem: changes with neuropathologic correlation.

Following trauma, imaging of brain stem lesions is often inconclusive. In a man who suffered a lethal accident, postmortem MR diffusion tensor (DT) imaging of the brain and neuropathologic examination were performed. DT imaging showed a disorganization of fibers in the brain stem that was not found in 2 controls and corresponded to changes on neuropathologic correlation. Diffusion tensor imaging provides an insight into the organization of myelinated structures of the CNS, potentially allowing diagnosis of traumatic fiber tract rupture.

Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging.

Convection-enhanced drug delivery (CEDD) is a novel approach to enhance the delivery of drugs directly into brain tumors. We have used diffusion-weighted MRI (DWMRI) to monitor the effects of intratumoral CEDD in three brain tumor patients treated with Taxol. Clear changes in the images and the water diffusion parameters were observed shortly after the initiation of treatment. Initially, a bright area corresponding to decreased diffusion appeared, followed by the appearance of a dark area of increased diffusion within the bright area. The time to appearance of the dark area varied among the patients, suggesting different response rates. In this work, we have demonstrated the feasibility of using DWMRI as a noninvasive tool to achieve unique early tissue characterization not attainable by other conventional imaging methods.

Effects of unilateral parietal lesions on spatial localization in the rat.

In the first of two experiments, rats with left or right parietal lesions and controls were tested in place and landmark navigation in the water maize. Right parietal lesions resulted in deficits in both tasks, but especially landmark navigation. Lateralized effects appeared mainly in latency to find the platform. Experiment 2 investigated the role of the corpus callosum. Split-brain rats with unilateral parietal lesions were tested on the same two tasks. Place and landmark deficits were particularly severe, but lateralization was weaker. Callosum section had its own effect, impairing the learning of both tasks. There appear to be additive effects of unilateral cortical lesions and bisection of the hemispheres. The impairment from left lesions equaled the right-lesion deficit because of the interruption of compensatory information from the intact right hemisphere and the effect of callosum section itself.

Hemodynamics in the abdominal aorta: a comparison of in vitro and in vivo measurements.

In vivo measurements of blood velocity profiles are difficult to obtain and interpret, since the parameters that govern the normally highly complex flow situation may not be fully quantified or understood at the time of measurement. In vitro flow models have been used often to better understand vascular hemodynamics. The assumptions made in the design of these models limit the applicability of the results. In this study, in vitro flow measurements made in a carefully designed model of the abdominal aorta were compared with in vivo measurements obtained with magnetic resonance imaging. In the suprarenal aorta, the velocity profiles were mostly forward and axisymmetric in both the in vitro and in vivo cases. In the infrarenal aorta, there was extensive flow reversal noted near the posterior wall in both cases. In the aortic bifurcation, two peaks of flow reversal were noted near the lateral posterior walls, and M-shaped velocity profiles were observed in late diastole. The in vitro and in vivo measurements exhibited good qualitative agreement. The in vitro model was accurate in modeling the in vivo hemodynamics of the abdominal aorta. The complex phenomena observed in vivo were explained on the basis of knowledge gained from the in vitro study.

Early experience modifies the lateralization of emotionality in parietal lesioned rats.

Male rats that were handled or not handled in infancy were given either unilateral parietal cortex lesions or unilateral parietal cortex lesions plus corpus callosum section as adults and tested on two independent measures of rodent emotionality, the Rodent Emotionality Rating scale and the open field. Lateralization of emotionality measured by open field ambulation and rearing only appeared in handled animals with right parietal cortex lesions plus transection of the corpus callosum. Notwithstanding, both the left and right parietal cortex were found to be involved in both aspects of emotionality when the corpus callosum was intact. It was the transection of the corpus callosum that brought out the interactive effects of the early experience manipulation and unilateral parietal lesion. Thus we have identified yet another role for the corpus callosum; one of mediating the effects of early experience in the lesioned brain.

Aortic flow velocity patterns in chronic aortic regurgitation: implications for Doppler echocardiography.

Aortic regurgitation is associated with retrograde diastolic flow in the aorta. Echocardiographic quantitative analysis of the magnitude of the flow reversal is believed to provide an estimate of severity of regurgitant disease despite variations in flow profiles. The purpose of this study was to evaluate the uniformity of flow patterns in the aorta of patients with aortic regurgitation and to investigate the relationship between these profiles and the echocardiographic estimates of flow reversal. Seventeen patients with chronic aortic regurgitation underwent cine-phase magnetic resonance imaging in an axial section through the ascending and descending aorta. The regurgitant fraction in the ascending aorta 4 cm above the aortic valve and the descending aorta were calculated from the velocity maps. These results were compared with data from nine individual sample volumes in the ascending and descending aorta. The magnetic resonance ascending aortic regurgitant fraction was compared with Doppler echocardiographic descending aortic flow velocity patterns. The descending aortic regurgitant fraction correlated only weakly with the ascending aortic regurgitant fraction (descending aortic regurgitant fraction = 0.62% ascending aortic regurgitant fraction + 0.04%; r = 0.75; p < 0.001). Regurgitant proportions in all sample volumes in the descending aorta, but not in the ascending aorta, were significantly related to the ascending aortic regurgitant fraction. The best descending aortic Doppler echocardiographic parameter for predicting ascending aortic regurgitant fraction was the end-diastolic velocity (end-diastolic velocity = 32.2 cm/sec. ascending aortic regurgitant fraction + 1.4 cm/sec; r = 0.94; p < 0.001). Pulsedwave Doppler sampling of descending aortic flow reflects severity of aortic regurgitant disease, in part the result of more uniform blood-velocity profiles in the descending aorta compared with the ascending aorta. The Doppler end-diastolic velocity in the descending aorta is a useful parameter of severity of aortic regurgitation.

MR line-scan diffusion imaging of the spinal cord in children.

Diffusion imaging has been widely used in the brain, but its application in the spinal cord has been limited. Using line-scan diffusion imaging (LSDI), a technique that is less sensitive to magnetic susceptibility and motion artifacts than are other diffusion techniques, we have successfully imaged the spinal cord in children. The apparent diffusion coefficient and relative diffusion anisotropy of the normal spinal cord were measured. LSDI was compared with echo-planar diffusion imaging of the spine in three patients.

MR line scan diffusion imaging of the brain in children.

BACKGROUND AND PURPOSE: MR imaging of the self-diffusion of water has become increasingly popular for the early detection of cerebral infarction in adults. The purpose of this study was to evaluate MR line scan diffusion imaging (LSDI) of the brain in children. METHODS: LSDI was performed in four volunteers and 12 patients by using an effective TR/TE of 2736/89.4 and a maximum b value of 450 to 600 s/mm2 applied in the x, y, and z directions. In the volunteers, single-shot echo planar imaging of diffusion (EPID) was also performed. The patients (10 boys and two girls) ranged in age from 2 days to 16 years (average age, 6.6 years). Diagnoses included acute cerebral infarction, seizure disorder, posttraumatic confusion syndrome, complicated migraine, residual astrocytoma, encephalitis, hypoxia without cerebral infarction, cerebral contusion, and conversion disorder. In all patients, routine spin-echo images were also acquired. Trace images and apparent diffusion coefficient maps were produced for each location scanned with LSDI. RESULTS: In the volunteers, LSDI showed less chemical-shift and magnetic-susceptibility artifact and less geometric distortion than did EPID. LSDI was of diagnostic quality in all studies. Diffusion abnormalities were present in five patients. Restricted diffusion was present in the lesions of the three patients with acute cerebral infarction. Mildly increased diffusion was present in the lesions of encephalitis and residual cerebellar astrocytoma. No diffusion abnormalities were seen in the remaining seven children. CONCLUSION: LSDI is feasible in children, provides high-quality diffusion images with less chemical-shift and magnetic-susceptibility artifact and less geometric distortion than does EPID, and complements the routine MR examination.

MR line-scan diffusion-weighted imaging of term neonates with perinatal brain ischemia.

BACKGROUND AND PURPOSE: MR diffusion-weighted imaging provides early demonstration of neonatal brain infarction. The evolution and limitations of diffusion-weighted imaging findings in newborns, however, have not been evaluated. Using line-scan diffusion imaging (LSDI), we investigated perinatal ischemic brain injury. METHODS: Nineteen term newborns (age, 9 hours to 8 days; mean age, 2.6 days) with perinatal brain ischemia were evaluated using LSDI (1520/62.5/1 [TR/TE/excitations]) (b maximum = 750 s/mm2) and T1- and T2-weighted spin-echo (conventional) MR imaging. Follow-up examinations were performed in seven patients and autopsy in one. Apparent diffusion coefficients (ADCs) were measured in deep gray matter, white matter, the cortex, and focal lesions. RESULTS: Based on conventional MR imaging or pathologic findings, patients were divided into two groups. Group 1 (n = 12) had symmetric/diffuse injury consistent with global hypoperfusion. Group 2 (n = 7) had focal/multifocal injury suggesting cerebrovascular occlusion. ADCs were abnormal at initial examination in 10 newborns in group 1 and in all newborns in group 2. The results of LSDI were abnormal before conventional MR imaging was performed in three newborns in group 1. ADCs were maximally decreased between days 1 and 3 in deep gray matter, perirolandic white matter, and focal lesions. Delayed decreases in ADCs were observed in subcortical white matter from days 4 through 10 in three patients in group 1. CONCLUSION: After global hypoperfusion, LSDI showed deep gray matter and perirolandic white matter lesions before conventional MR imaging. LSDI may underestimate the extent of injury, however, possibly because of variations in the compartmentalization of edema, selective vulnerability, and delayed cell death. Differences in LSDI of symmetric/diffuse and focal/multifocal lesions may reflect differences in pathophysiology or timing of the injury. These findings may have implications for acute interventions.

Multivariate analysis of putative measures of activity, exploration, emotionality, and spatial behavior in the hooded rat (Rattus norvegicus).

Hooded rats were tested in six situations representing the variables of activity, exploration, emotionality, and spatial preference, detection of change, and learning. The activity, exploration, and emotionality variables and spatial variables were analyzed in separate multivariate analyses, followed by an analysis of the entire set. The first of these resulted in four components: activity, exploration and emotionality, reactivity to handling, and autonomic reactivity (defecation). Four components, defined by the following variables, emerged from the spatial analysis: (a) the tendency to circle, circling direction, and spatial learning; (b) heading error in spatial learning and reversal and open-field directional preference; (c) spatial reversal and direction of turn to escape restraint; and (d) detection of change in spatial arrangement and directional preference in the detection task. The final analysis investigated relations between the activity, exploration, and emotionality variables and the spatial variables, finding only two. The clear dimensionality of these behavioral repertoires emphasizes how important it is to recognize the distinctions among them.

Visualization and quantification of the human blood flow by magnetic resonance imaging.

Magnetic Resonance Imaging (MRI) offers new possibilities for the visualization and the noninvasive quantification of the blood flow in human vessels. By the application of conventional gradient echo sequences with electrocardiographic gating on a 1.5 Tesla whole body MRI system the flow induced phase shifts in the ascending and the abdominal aorta are analyzed. The instantaneous two-dimensional velocity profiles and the instantaneous flow rates are determined in a series of subsequent images with high temporal resolution throughout the cardiac cycle. For the flow analysis in further vessels and for the analysis of more complex flow patterns, as they occur in bifurcations or stenoses, a new MR flow imaging technique called FAcE with extremely short echo times is introduced and the first results of flow examinations in a bifurcation phantom and in the carotid artery are presented.

FID-acquired-echos (FAcE): a short echo time imaging method for flow artefact suppression.

The FID-Acquired-Echo sequence (FAcE) is a magnetic resonance imaging technique using fractional-echo acquisitions, with sequential separate sampling of the right and left k-space half planes. It reduces the minimal echo times by about a factor of two, compared to conventional full-(gradient)-echo sampling schemes. With this sequence, implemented on a commercial 1.5 Tesla whole body system, high resolution images are acquired with typical echo times between 3 and 4.5 msec. Using short echo times the signal dephasing caused by velocity and higher order spin motion is reduced. Further, due to the modified sampling scheme, the sequence exhibits, for triggered studies, partially a compensation of motion-induced phase shifts in the frequency-encoding direction. Thus, the sequence offers an alternative means for the reduction of motion-induced image artefacts to the use of flow compensating gradients, which usually makes a sequence more sensitive to higher order motion and introduces further eddy currents. Besides potential application for imaging of nuclei and tissues with short T2 relaxation times, and non-ECG-triggered in-flow angiography, the main application seems to be triggered-phase contrast imaging with focus on quantitation of blood flow. Its usefulness is largest in cases with irregular flow patterns, where considerable in-plane flow occurs.

Accurate velocity mapping with FAcE.

Spin dislocation between the slice selection, phase encoding, and frequency encoding is a source of image distortions. Two strategies can be pursued to improve the appearance of moving spins in an image. Either the sequence is made equally sensitive to velocity-dependent dislocation artifacts for all spatial directions or the sensitivity is reduced with a shorter echo time. The first approach increases the dislocation for the phase-encoding direction and is therefore not useful if velocity maps with minimal distortion are the goal. FAcE (FID acquired echoes) is a sequence with separate sampling of the left and right k-space half-planes that allows for very short echo times. It was applied for velocity mapping of flow in the slice select direction. Special attention was paid to a compact design of the velocity-encoding select gradient to achieve short echo times even with high velocity sensitivity. Artifacts introduced by in-plane motion were studied for FAcE and conventional gradient-echo sequences, both in phantom experiments and simulation. FAcE allows for very short echo times with inherent motion compensation of the frequency-encoding gradient. Thus, both motion-related dislocation artifacts and signal voids due to coherence loss in regions with irregular flow are minimal.

Biexponential apparent diffusion coefficient parametrization in adult vs newborn brain.

The decay of brain water signal with b-factor in adult and newborn brains has been measured over an extended b-factor range. Measurements of the apparent diffusion coefficient (ADC) decay curves were made at 16 b-factors from 100 to 5000 s/mm(2) along three orthogonal directions using a line scan diffusion imaging (LSDI) sequence to acquire data from 0.09 ml voxels in a mid-brain axial slice. Regions-of-interest (ROIs) in cortical gray (CG) and white matter in the internal capsule (IC) were selected for ADC decay curve analyses using a biexponential fitting model over this extended b-factor range. Measures of the fast and slow ADC component amplitudes and the traces of the fast and slow diffusion coefficients were obtained from CG and IC ROIs in both adults and newborns. The ADC decay curves from the newborn brain regions were found to have a significantly higher fraction of the fast diffusion ADC component than corresponding regions in the adult brain. The results demonstrate that post-natal brain development has a profound affect on the biexponential parameters which characterize the decay of water signal over an extended b-factor range in both gray and white matter.

Prenatal binge-like alcohol exposure alters neurochemical profiles in fetal rat brain.

The majority of studies examining the effects of prenatal exposure to alcohol on neurotransmitter levels have furnished results that are divergent (increase, decrease or no change). The present study assessed six neurochemical compounds [norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), gamma-aminobutyric acid (GABA)] from the same brain tissue. Pregnant Sprague-Dawley rats were given 5.1 g/kg alcohol (by gavage) either daily from embryonic day 1 (E1) through E20 or E20 only. In addition, pairfed/intubated (PF/INT) and ad lib chow (Chow) groups were included as controls. The dams were sacrificed and the fetuses were removed on E20. Binge-like alcohol exposure throughout gestation (E1-E20) produced significantly higher brain to body weight ratios compared with all other groups. Alcohol exposure did not produce changes in NE levels, although the E1-E20 exposure to alcohol reduced the contents of DA and 5-HT compared with the PF/INT and Chow controls. In addition, the E20 alcohol treatment reduced both DA and 5-HT levels compared with the E1-E20 alcohol treatment. DOPAC and 5-HIAA contents were affected by the prenatal treatments insofar as the 5-HIAA levels were decreased in E/1-20 and E20 animals relative to both controls, while the DOPAC levels were decreased in E/1-20, E20 and PF/INT groups compared to the Chow group; however, both metabolites were unaffected by the difference in alcohol treatment duration. Moreover, GABA levels were increased in fetuses exposed to alcohol from E1-E20 compared with all other groups. Collectively, these findings suggest that binge-like alcohol exposure prior to and during neurotransmitter development affects the baseline content of several neurotransmitters.

Prenatal alcohol treatment attenuated postnatal cocaine-induced elevation of dopamine concentration in nucleus accumbens: a preliminary study.

Prenatal alcohol exposure has been shown to damage the developing central nervous system (CNS) in a variety of ways, including neuroanatomical anomalies, neurochemical imbalance, and neuropharmacological dysfunction. The present study investigated one of the functional aspects of dopaminergic system in neonatal rats exposed prenatally to a binge-like alcohol paradigm by measuring dopamine concentrations following a single postnatal cocaine challenge. Pregnant Sprague-Dawley rats were given daily intragastric intubations of 5.1 g/kg alcohol solution from embryonic day (E) 1 to 20. Pair-fed and ad lib-fed animals served as controls. On E33 (usually postnatal day 10), offspring from all groups were given injections (IP) of either 0, 20, or 40 mg/kg cocaine. Animals were sacrificed and the substantia nigra/ventral tegmental area (SN/VTA) and nucleus accumbens (NAc) were dissected for the determination of dopamine concentrations using HPLC. Basal dopamine levels (0 mg/kg cocaine group) did not alter as a function of prenatal alcohol treatment in either region. However, acute cocaine injection increased the dopamine content in NAc, but not in SN/VTA, in ad lib-fed animals, and this elevation in dopamine level was significantly attenuated by prenatal alcohol treatment in both female and male animals, and by prenatal pair-fed treatment in male animals. Taken together, these results indicate that there appears to be a regional difference in acute cocaine-induced dopamine elevation, and prenatal binge-like alcohol exposure significantly alters the functional responsiveness of dopaminergic system in NAc. Furthermore, these data suggest that male offspring may be more sensitive to stress-associated or nutritional influences during gestation.

Prenatal binge-like alcohol exposure in the rat results in region-specific deficits in brain growth.

Children of women who abuse alcohol during pregnancy may be affected by varying degrees of neurological abnormality, even if they are not diagnosed with Fetal Alcohol Syndrome. The extent of the behavioral deficits of the affected offspring may be a function of several factors, such as the differential vulnerability of the various regions of the brain-to-alcohol insult. In this study, groups of timed-pregnant rats were exposed to different doses of alcohol (EtOH 2.25, EtOH 4.5, EtOH 6.5 g/kg/day) or control conditions (maltose dextrin solution or no treatment) from embryonic day 1 (E1: sperm positive) to E20. On E33 (usually postnatal day 10), all pups were perfused. Their brains were removed, dissected into forebrain, cerebellum, and brainstem, and weighed. Blood alcohol concentrations (BACs) were measured on 4 different days of gestation, but the peak BACs across gestation for the three alcohol-treated groups averaged 142, 294, and 413 mg/dl for the EtOH 2.25, EtOH 4.5, and EtOH 6.5 g/kg groups, respectively. Analysis of the body weight data indicated that pups in the EtOH 6.5 g/kg group had a greater somatic growth deficit than pups from all other groups. Although the whole brain, forebrain, cerebellum, and brainstem weights of pups in the EtOH 6.5 g/kg group were significantly smaller than those in the control groups, within-treatment group analyses indicated that the cerebella of pups in the EtOH 6.5 g/kg group were more severely affected than were their forebrains or brainstems. The analyses of the brain region to body weight ratios revealed again that the cerebellum-to-body-weight ratio of pups in the EtOH 6.5 g/kg group was more severely affected than the forebrain or brainstem to body weight ratios. Collectively, these data lend support to the view that gross regions of the brain are differentially vulnerable to alcohol insult during the first two trimesters equivalent, and suggest that the cerebellum is vulnerable to injury from exposure to high BACs during a developmental period other than the third trimester equivalent.

Processing and visualization for diffusion tensor MRI.

This paper presents processing and visualization techniques for Diffusion Tensor Magnetic Resonance Imaging (DT-MRI). In DT-MRI, each voxel is assigned a tensor that describes local water diffusion. The geometric nature of diffusion tensors enables us to quantitatively characterize the local structure in tissues such as bone, muscle, and white matter of the brain. This makes DT-MRI an interesting modality for image analysis. In this paper we present a novel analytical solution to the Stejskal-Tanner diffusion equation system whereby a dual tensor basis, derived from the diffusion sensitizing gradient configuration, eliminates the need to solve this equation for each voxel. We further describe decomposition of the diffusion tensor based on its symmetrical properties, which in turn describe the geometry of the diffusion ellipsoid. A simple anisotropy measure follows naturally from this analysis. We describe how the geometry or shape of the tensor can be visualized using a coloring scheme based on the derived shape measures. In addition, we demonstrate that human brain tensor data when filtered can effectively describe macrostructural diffusion, which is important in the assessment of fiber-tract organization. We also describe how white matter pathways can be monitored with the methods introduced in this paper. DT-MRI tractography is useful for demonstrating neural connectivity (in vivo) in healthy and diseased brain tissue.