Exploratory Multisite MR Spectroscopic Imaging Shows White Matter Neuroaxonal Loss Associated with Complications of Type 1 Diabetes in Children.

BACKGROUND AND PURPOSE: Type 1 diabetes affects over 200,000 children in the United States and is associated with an increased risk of cognitive dysfunction. Prior single-site, single-voxel MRS case reports and studies have identified associations between reduced NAA/Cr, a marker of neuroaxonal loss, and type 1 diabetes. However, NAA/Cr differences among children with various disease complications or across different brain tissues remain unclear. To better understand this phenomenon and the role of MRS in characterizing it, we conducted a multisite pilot study. MATERIALS AND METHODS: In 25 children, 6-14 years of age, with type 1 diabetes across 3 sites, we acquired T1WI and axial 2D MRSI along with phantom studies to calibrate scanner effects. We quantified tissue-weighted NAA/Cr in WM and deep GM and modeled them against study covariates. RESULTS: We found that MRSI differentiated WM and deep GM by NAA/Cr on the individual level. On the population level, we found significant negative associations of WM NAA/Cr with chronic hyperglycemia quantified by hemoglobin A1c (P < .005) and a history of diabetic ketoacidosis at disease onset (P < .05). We found a statistical interaction (P < .05) between A1c and ketoacidosis, suggesting that neuroaxonal loss from ketoacidosis may outweigh that from poor glucose control. These associations were not present in deep GM. CONCLUSIONS: Our pilot study suggests that MRSI differentiates GM and WM by NAA/Cr in this population, disease complications may lead to neuroaxonal loss in WM in children, and deeper investigation is warranted to further untangle how diabetic ketoacidosis and chronic hyperglycemia affect brain health and cognition in type 1 diabetes.

Validation of diffusion tensor MRI in the central nervous system using light microscopy: quantitative comparison of fiber properties.

Diffusion tensor imaging (DTI) provides an indirect measure of tissue structure on a microscopic scale. To date, DTI is the only imaging method that provides such information in vivo, and has proven to be a valuable tool in both research and clinical settings. In this study, we investigated the relationship between white matter structure and diffusion parameters measured by DTI. We used micrographs from light microscopy of fixed, myelin-stained brain sections as a gold standard for direct comparison with data from DTI. Relationships between microscopic tissue properties observed with light microscopy (fiber orientation, density and coherence) and fiber properties observed by DTI (tensor orientation, diffusivities and fractional anisotropy) were investigated. Agreement between the major eigenvector of the tensor and myelinated fibers was excellent in voxels with high fiber coherence. In addition, increased fiber spread was strongly associated with increased radial diffusivity (p = 6 × 10(-6)) and decreased fractional anisotropy (p = 5 × 10(-8)), and was weakly associated with decreased axial diffusivity (p = 0.07). Increased fiber density was associated with increased fractional anisotropy (p = 0.03), and weakly associated with decreased radial diffusivity (p < 0.06), but not with axial diffusivity (p = 0.97). The mean diffusivity was largely independent of fiber spread (p = 0.24) and fiber density (p = 0.34).

LEARNING 3D WHITE MATTER MICROSTRUCTURE FROM 2D HISTOLOGY.

Histological analysis is typically the gold standard for validating measures of tissue microstructure derived from magnetic resonance imaging (MRI) contrasts. However, most histological investigations are inherently 2-dimensional (2D), due to increased field-of-view, higher in-plane resolutions, ease of acquisition, decreased costs, and a large number of available contrasts compared to 3-dimensional (3D) analysis. Because of this, it would be of great interest to be able to learn the 3D tissue microstructure from 2D histology. In this study, we use diffusion MRI (dMRI) of a squirrel monkey brain and corresponding myelin stained sections in combination with a convolution neural network to learn the relationship between the 3D diffusion estimated axonal fiber orientation distributions and the 2D myelin stain. We find that we are able to estimate the 3D fiber distribution with moderate to high angular agreement with the ground truth (median angular correlation coefficients of 0.48 across the unseen slices). This network could be used to validate dMRI neuronal structural measurements in 3D, even if only 2D histology is available for validation. Generalization is possible to transfer this network to human stained sections to infer the 3D fiber distribution at resolutions currently unachievable with dMRI, which would allow diffusion fiber tractography at unprecedented resolutions. We envision the use of similar networks to learn other 3D microstructural measures from an array of potential common 2D histology contrasts.

Expertise for cars and birds recruits brain areas involved in face recognition.

Expertise with unfamiliar objects ('greebles') recruits face-selective areas in the fusiform gyrus (FFA) and occipital lobe (OFA). Here we extend this finding to other homogeneous categories. Bird and car experts were tested with functional magnetic resonance imaging during tasks with faces, familiar objects, cars and birds. Homogeneous categories activated the FFA more than familiar objects. Moreover, the right FFA and OFA showed significant expertise effects. An independent behavioral test of expertise predicted relative activation in the right FFA for birds versus cars within each group. The results suggest that level of categorization and expertise, rather than superficial properties of objects, determine the specialization of the FFA.

Activation of the middle fusiform 'face area' increases with expertise in recognizing novel objects.

Part of the ventral temporal lobe is thought to be critical for face perception, but what determines this specialization remains unknown. We present evidence that expertise recruits the fusiform gyrus 'face area'. Functional magnetic resonance imaging (fMRI) was used to measure changes associated with increasing expertise in brain areas selected for their face preference. Acquisition of expertise with novel objects (greebles) led to increased activation in the right hemisphere face areas for matching of upright greebles as compared to matching inverted greebles. The same areas were also more activated in experts than in novices during passive viewing of greebles. Expertise seems to be one factor that leads to specialization in the face area.

Levels of categorization in visual recognition studied using functional magnetic resonance imaging.

BACKGROUND: Recent functional neuroimaging results implicate part of the ventral temporal lobe of the brain in face recognition, and have, together with neurophysiological findings, been used as evidence for a face-specific neural module in the brain. Experimental designs, however, have often failed to distinguish between the class of the object used as the stimulus (face or non-face) and the level of categorization at which the stimulus is recognized (the 'basic' level, such as 'bird', at which familiar objects are first recognized, or more subordinate levels - 'sparrow', for example - which require additional perceptual processing). We have used echo-planar functional magnetic resonance imaging to compare brain activation for the matching of non-face objects with subordinate-level and basic-level descriptors. RESULTS: The additional visual processing required to verify the subordinate level of a picture over its basic level was associated with activation of the fusiform and inferior temporal gyri (FIT) as well as the temporal poles. These areas correspond closely to those previously implicated in the processing of facial images. CONCLUSIONS: Our results indicate that areas of the ventral visual pathway that have been associated with face recognition are sensitive to manipulations of the categorization level of non-face objects. This idea offers an alternative to the dominant view that FIT may be organized according to conceptual categories, and our results establish the importance of manipulating task requirements when evaluating a 'neural module' hypothesis.

Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome.

BACKGROUND: Recognition of individual faces is an integral part of both interpersonal interactions and successful functioning within a social group. Therefore, it is of considerable interest that individuals with autism and related conditions have selective deficits in face recognition (sparing nonface object recognition). METHOD: We used functional magnetic resonance imaging (fMRI) to study face and subordinate-level object perception in 14 high-functioning individuals with autism or Asperger syndrome (the autism group), in comparison with 2 groups of matched normal controls (normal control group ] [NC1] and normal control group 2 [NC2]) (n = 14 for each). Regions of interest (ROIs) were defined in NC1 and then applied in comparisons between NC2 and the autism group. Regions of interest were also defined in NC2 and then applied to comparisons between NC1 and the autism group as a replication study. RESULTS: In the first set of comparisons, we found significant task x group interactions for the size of activation in the right fusiform gyrus (FG) and right inferior temporal gyri (ITG). Post hoc analyses showed that during face (but not object) discrimination, the autism group had significantly greater activation than controls in the right ITG and less activation of the right FG. The replication study showed again that the autism group used the ITG significantly more for processing faces than the control groups, but for these analyses, the effect was now on the left side. Greater ITG activation was the pattern found in both control groups during object processing. CONCLUSIONS: Individuals with autism spectrum disorders demonstrate a pattern of brain activity during face discrimination that is consistent with feature-based strategies that are more typical of nonface object perception.

A functional magnetic resonance imaging study of tic suppression in Tourette syndrome.

BACKGROUND: The inability to inhibit unwanted behaviors and impulses produces functional debility in a broad range of neuropsychiatric disorders. A potentially important model of impulse control is volitional tic suppression in Tourette syndrome. METHODS: Tic suppression was studied in 22 adult subjects with Tourette syndrome by using functional magnetic resonance imaging. Images acquired during periods of voluntary tic suppression were compared with images acquired when subjects allowed the spontaneous expression of their tics. The magnitudes of signal change in the images were then correlated with measures of the severity of tic symptoms. CONCLUSIONS: Significant changes in signal intensity were seen in the basal ganglia and thalamus and in anatomically connected cortical regions believed to subserve attention-demanding tasks. The magnitudes of regional signal change in the basal ganglia and thalamus correlated inversely with the severity of tic symptoms. These findings suggest that the pathogenesis of tics involves an impaired modulation of neuronal activity in subcortical neural circuits.

An fMRI study of Stroop word-color interference: evidence for cingulate subregions subserving multiple distributed attentional systems.

BACKGROUND: The goal of this study was to model the functional connectivity of the neural systems that subserve attention and impulse control. Proper performance of the Stroop Word-Color Interference Task requires both attention and impulse control. METHODS: Word-color interference was studied in 34 normal adult subjects using functional magnetic resonance imaging. RESULTS: Interregional correlation analyses suggested that the anterior cingulate is coupled functionally with multiple regions throughout the cerebrum. A factor analysis of the significant regional activations further emphasized this functional coupling. The cingulate or related mesial frontal cortices loaded on each of the seven factors identified in the factor analysis. Other regions that loaded significantly on these factors have been described previously as belonging to anatomically connected circuits believed to subserve sensory tuning, receptive language, vigilance, working memory, response selection, motor planning, and motor response functions. These seven factors appeared to be oriented topographically within the anterior cingulate, with sensory, working memory, and vigilance functions positioned more rostrally, and response selection, motor planning, and motor response positioned progressively more caudally. CONCLUSIONS: These findings support a parallel distributed processing model for word-color interference in which portions of the anterior cingulate cortex modify the strengths of multiple neural pathways used to read and name colors. Allocation of attentional resources is thought to modify pathway strengths by reducing cross-talk between information processing modules that subserve the competing demands of reading and color naming. The functional topography of these neural systems observed within the cingulate argues for the presence of multiple attentional subsystems, each contributing to improved task performance. The topography also suggests a role for the cingulate in coordinating and integrating the activity of these multiple attentional subsystems.

Streptococcal toxic shock syndrome: a description of 14 cases from North Yorkshire, UK.

OBJECTIVE: To analyze the clinical and laboratory features of patients diagnosed with streptococcal toxic shock syndrome (TSS) in North Yorkshire from 1986 to 1999. METHODS: Records of patients with features satisfying the published criteria for streptococcal TSS were reviewed from laboratory and clinical records made at the time and from the hospital case notes. Isolates of streptococci were analyzed for serotype and genes encoding for the production of streptococcal pyrogenic exotoxins. RESULTS: Fourteen patients satisfied the entry criteria. In one district, where the data were complete, the annual incidence of detected streptococcal TSS rose from 1.1 to 9.5 cases per million population in the 1990s. TSS was associated with various M serotypes of group A streptococci and various exotoxin genotypes. Two cases (14% of the series) were associated with severe group G streptococcal infection. The fatality rate was 64%, and the mode of time to death was 4 days. Local tissue necrosis occurred in 71% of cases, including necrotizing fasciitis, intrathoracic and intra-abdominal forms. Non-steroidal anti-inflammatory drugs (NSAIDs) had been taken around the time of onset of disease by 92% of the patients with TSS. CONCLUSIONS: There has been a dramatic increase in the number of detected cases of streptococcal TSS over the 14 years since the first case was recognized here. There was a wide range of invasive forms of infection, a high fatality rate even in fit young adults, and a rapid course from onset to death. There was a high association of TSS with aggressive streptococcal infection producing local tissue necrosis.

Measurements of restricted diffusion using an oscillating gradient spin-echo sequence.

An oscillating gradient spin-echo (OGSE) pulse sequence was used to measure the apparent diffusion coefficient (D(app)) of water in the short diffusion time regime in the presence of restrictions. The diffusion coefficients of water in a simple water sample and a water and oil mixture were measured to be the same for different periods of the gradient oscillation, as expected when there are no restriction effects. The D(app) of water in the spaces between closely packed beads was also measured as a function of the gradient oscillation periods in the range 11 to 80 ms. The D(app) of water in restricted systems varies with the period of the gradient oscillation and the dispersion depends on the scale of the restriction. For a sample of packed beads of diameter 9.1 +/- 0.7 microm, the pore surface-to-volume ratio was estimated experimentally by this method to be 1.3 +/- 0.1 microm(-1), corresponding to a mean pore diameter of 6.4 +/- 0.7 microm. A Monte Carlo computer simulation of the NMR OGSE signal from the spins diffusing in a system of compartments was also implemented and the D(app) demonstrated similar behavior with gradient oscillation periods.

Density matrix simulations of the effects of J coupling in spin echo and fast spin echo imaging.

A computer simulation has been used to calculate the effects of J coupling on the amplitudes of echoes produced by CPMG sequences. The program computes the evolution of the density matrix for different pulse intervals and can predict the signals obtainable from spin systems of any size and complexity. Results from the simulation confirm the prediction that a decrease in the effects of J coupling is largely responsible for the bright fat signal seen in fast spin echo imaging at high pulse rates. The effects of J coupling on CPMG echotrains are examined for A3B2 and A3B2C2 spin systems over a wide range of J coupling and chemical shift values and pulse spacings. The effects of J coupling on the point spread function obtained with fast spin echo imaging are also discussed.

Analysis of J coupling-induced fat suppression in DIET imaging.

The DIET (or dual interval echo train) sequence, a modification of the fast spin echo (FSE) sequence that selectively reduces signal from fat in MR images, has been investigated. The DIET sequence uses an initial echo spacing longer than that of a conventional FSE sequence, thus allowing J coupling-induced dephasing to take effect. The sequence is evaluated theoretically, and its effectiveness on a hydrocarbon (1-pentene) is demonstrated numerically using density matrix calculations. The sequence is also evaluated experimentally using in vitro solutions and in vivo imaging. The efficacy of the sequence is compared for different lipid chemical structures, field strengths, and pulse sequence parameters.

An outbreak of puerperal fever caused by group G streptococci.

An outbreak of puerperal fever caused by group G streptococci is described. Transmission of the organism may have occurred via contamination of automated douches. When these were disinfected and kept free of the organism the outbreak ended abruptly.

Respiratory effects in human functional magnetic resonance imaging due to bulk susceptibility changes.

Functional magnetic resonance imaging relies on detecting small changes in the signal in the presence of noise from various sources. It has been shown that periodic variations in the signal at the respiratory frequency occur in the brain and various techniques have been proposed to remove them. However, the precise mechanism by which respiration affects the fMRI signal has not yet been proven. Here, we explore the nature of respiratory signal variations and the artefacts they produce in brain images. Our results demonstrate conclusively that bulk susceptibility variations in the lungs during respiration cause variations in the static magnetic field within the brain tissue. These variations in field strength and homogeneity lead to a shift of the image and a shading of image intensity in the phase encoding direction. These artefacts, if left uncorrected, may lead to the production of spurious activations and/or decreased statistical significance of true activations in fMRI. In addition, these results suggest that respiration effects may not necessarily be well characterized as simple additive noise and that an alternative model based on the physical origins of susceptibility variations may be more appropriate.

A model for susceptibility artefacts from respiration in functional echo-planar magnetic resonance imaging.

Respiration causes variations in the signals acquired during magnetic resonance imaging (MRI) and therefore is a significant source of noise in functional brain imaging. A primary component of respiratory noise may arise from variations of bulk susceptibility or air volume in the chest. Here we investigate the nature of the image artefacts that can be caused by such changes. We develop a simple model which attempts to mimic the effects of variations in susceptibility and volume during respiration. Theoretical calculations, computer simulations and imaging experiments with this model show that small variations in susceptibility within the thorax from alterations in the paramagnetism of cavity gas may lead to a shift of the image on the order of 0.1 pixels as well as a shading of the intensity by +/-1%. These effects are observed to be predominant in the phase-encoding direction. They may lead to the production of spurious activations in functional MRI and are likely to be of more importance at higher field strengths.

Factors influencing contrast in fast spin-echo MR imaging.

Multi-echo pulse sequences for producing T2-weighted images in much reduced imaging times have recently been developed for routine clinical use. A number of recent articles have described the contrast obtained with fast spin-echo (FSE) sequences and have generally indicated that they depict tissues very similarly to conventional spin-echo (SE) imaging. There are, however, some important differences in contrast between some tissues in FSE images. This work presents a detailed study of the contrast obtained with FSE imaging sequences and examines the image sequence and tissue parameters which influence contrast. The use of multiple refocusing pulses produces several subtle effects not seen in conventional SE imaging sequences, and in this study the precise nature and extent of such effects are described. The relative contributions to image contrast of magnetization transfer, the decoupling of J-modulation effects, the production of stimulated echoes and direct saturation effects, of diffusion and of the effects of the differential attenuation of different spatial frequencies, are each quantified. The mechanisms responsible for the brighter fat signal seen in FSE images, as well as the loss of signal from some other tissues, are explained. Computer simulations, phantom experiments, and clinical images are all used to support the conclusions.

Effects of cell volume fraction changes on apparent diffusion in human cells.

Diffusion-weighted imaging was used to study the relationship between apparent diffusion coefficient (ADC) and cell volume fraction in cell suspensions and packed arrays. Cell volume fraction was varied by changing extracellular fluid osmolarity (for human glial cells) and by changing cell density (for human glial and red blood cells). In packed arrays of glial cells, ADC increased 10% when cells shrank and decreased 13% when cells swelled. ADC decreased 34% as cell density increased from 0 to 72%. In erythrocyte suspensions, ADC decreased 90% as the cell density increased from 0 to 89%. These results agree with theoretical predictions.

Functional brain imaging at 1.5 T using conventional gradient echo MR imaging techniques.

There is considerable interest in the use of MR imaging to study brain function. Recently, it has been demonstrated that small changes in signal intensity occur in the visual cortex in T2*-weighted imaging in response to appropriate visual stimuli. Similar responses to activation have also been recorded in motor cortex as well as frontal lobes. To date most of these studies have been carried out at very high field strength or they have used echo planar imaging. We report our preliminary results showing that the effects of activation of visual and motor areas of the brains of normal volunteers can be recorded using conventional MR imaging methods on a standard 1.5 T clinical scanner. Using gradient-echo imaging sequences, we have been able to map activated visual and motor cortex with high spatial resolution in multiple planes, and are using this technique to examine the relationship between physiological response and stimulus parameters. Signal changes of the order of 2-12% in images with TE = 45 msec, TR = 120 msec, and alpha = 40 degrees, permit excellent depiction of the regions affected.

The relationship of problems in biomedical MRI to the study of porous media.

The NMR methods that are used to characterize inanimate porous media measure relaxation times and related phenomena and material transport, fluid displacement and flow. Biological tissues are comprised of multiple small, fluid-filled compartments, such as cells, that restrict the movement of the bulk solvent water and whose constituents influence water proton relaxation times via numerous interactions with macromolecular surfaces. Several of the methods and concepts that have been developed in one field of application are also of great value in the other, and it may be expected that technical developments that have been spurred by biomedical applications of MR imaging will be used in the continuing study of porous media. Some recent specific studies from our laboratory include the development of multiple quantum coherence methods for studies of ordered water in anisotropic macromolecular assemblies, studies of the degree of restriction of water diffusion in cellular systems, multiple selective inversion imaging to depict the ratios of proton pool sizes and rates of magnetization transfer between proton populations, and diffusion tensor imaging to depict tissue anisotropies. These illustrate how approaches to obtain structural information from biological media are also relevant to porous media. For example, the recent development of oscillating gradient spin echo techniques (OGSE), an approach that extends our ability to resolve apparent diffusion changes over different time scales in tissues, has also been used to compute surface to volume measurements in assemblies of pores. Each of the new methods can be adapted to provide spatially resolved quantitative measurements of properties of interest, and these can be efficiently acquired with good accuracy using fast imaging methods such as echo planar imaging. The community of NMR scientists focused on applications to porous media should remain in close communication with those who use MRI to study problems in biomedicine, to their mutual benefits.