Vincent J. Schmithorst

Sirolimus for Angiomyolipoma in Tuberous Sclerosis Complex or Lymphangioleiomyomatosis

BACKGROUND Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling. METHODS We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed. RESULTS Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections. CONCLUSIONS Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)

Cognitive functions correlate with white matter architecture in a normal pediatric population : A diffusion tensor MRI study

A possible relationship between cognitive abilities and white matter structure as assessed by magnetic resonance diffusion tensor imaging (DTI) was investigated in the pediatric population. DTI was performed on 47 normal children ages 5–18. Using a voxelwise analysis technique, the fractional anisotropy (FA) and mean diffusivity (MD) were tested for significant correlations with Wechsler full‐scale IQ scores, with subject age and gender used as covariates. Regions displaying significant positive correlations of IQ scores with FA were found bilaterally in white matter association areas, including frontal and occipito‐parietal areas. No regions were found exhibiting correlations of IQ with MD except for one frontal area significantly overlapping a region containing a significant correlation with FA. The positive direction of the correlation with FA is the same as that found previously with age, and indicates a positive relationship between fiber organization and/or density with cognitive function. The results are consistent with the hypothesis that regionally specific increased fiber organization is a mechanism responsible for the normal development of white matter tracts. Hum Brain Mapp, 2005.

Spatial variation in cartilage T2 of the knee

Technical limitations imposed by resolution and B1 homogeneity have thus far limited quantitative in vivo T2 mapping of cartilage to the patella. The purpose of this study is to develop T2 mapping of the femoral/tibial joint and assess regional variability of cartilage T2 in the knee. Quantitative in vivo T2 mapping of the knee was performed on 15 asymptomatic adults (age, 22–44) using a 3T MR scanner. There is a consistent pattern of spatial variation in cartilage T2 with longer values near the articular surface. The greatest variation occurs in the patella, where T2 increases from 45.3 ± 2.5 msec at a normalized distance of 0.33–67 ± 5.5 msec at a distance of 1.0. These results demonstrate feasibility of performing in vivo T2 mapping of femoral tibial cartilage. Except for the superficial 15% where T2 values are lower, the spatial variation in T2 of femoral and tibial cartilage is similar to patellar cartilage. J. Magn. Reson. Imaging 2001;14:50–55.

fMRI study of language lateralization in children and adults.

Language lateralization in the brain is dependent on family history of handedness, personal handedness, pathology, and other factors. The influence of age on language lateralization is not completely understood. Increasing left lateralization of language with age has been observed in children, while the reverse has been noted in healthy young adults. It is not known whether the trend of decreasing language lateralization with age continues in the late decades of life and at what age the inflection in language lateralization trend as a function of age occurs. In this study, we examined the effect of age on language lateralization in 170 healthy right‐handed children and adults ages 5–67 using functional MRI (fMRI) and a verb generation task. Our findings indicate that language lateralization to the dominant hemisphere increases between the ages 5 and 20 years, plateaus between 20 and 25 years, and slowly decreases between 25 and 70 years. Hum Brain Mapp, 2005.

Assessment of spatial normalization of whole-brain magnetic resonance images in children.

Commonly used frameworks for spatial normalization of brain imaging data (e.g., Talairach‐space) are based on one or more adult brains. As pediatric brains are different in size and shape from adult brains and continue to develop through childhood, we aimed to assess the influence of age on various spatial normalization parameters. One hundred forty‐eight healthy children aged 5–18 years were included in this study. The linear scaling parameters and the deformations from the non‐linear spatial normalization to both a standard adult and a custom pediatric template were analyzed within SPM99. The effect of using a brain mask on the linear and of using different levels of constraint on the non‐linear spatial normalization was assessed. Of the linear scaling factors, only the X‐dimension (left–right) showed a significant age‐correlation when based on brain tissue, whereas the overall scaling was not correlated with age. When based on the whole head, a very strong age‐effect can be found in all dimensions. Non‐linear deformations also show localized correlations with age, most pronounced in parietal and frontal areas. The total amount of volume change is significantly lower when using a pediatric template. It is also substantially influenced by the degree of regularization that is exerted on the spatial normalization parameters. Our results suggest that in the cortical areas showing a strong correlation of deformation with age, caution should be used in assigning imaging results in children to a specific morphological structure. Also, to minimize the amount of deformation during non‐linear spatial normalization, a pediatric template should be used. Further implications of our findings on developmental neuroimaging studies are discussed. Hum. Brain Mapping 17:48–60, 2002.

Simultaneous correction of ghost and geometric distortion artifacts in EPI using a multiecho reference scan

A computationally efficient technique is described for the simultaneous removal of ghosting and geometrical distortion artifacts in echo-planar imaging (EPI) utilizing a multiecho, gradient-echo reference scan. Nyquist ghosts occur in EPI reconstructions because odd and even lines of k-space are acquired with opposite polarity, and experimental imperfections such as gradient eddy currents, imperfect pulse sequence timing, B/sub 0/ field inhomogeneity, susceptibility, and chemical shift result in the even and odd lines of k-space being offset by different amounts relative to the true center of the acquisition window. Geometrical distortion occurs due to the limited bandwidth of the EPI images in the phase-encode direction. This distortion can be problematic when attempting to overlay an activation map from a functional magnetic resonance imaging experiment generated from EPI data on a high-resolution anatomical image. The method described here corrects for geometrical distortion related to B/sub 0/ inhomogeneity, gradient eddy currents, radio-frequency pulse frequency offset, and chemical shift effect. The algorithm for removing ghost artifacts utilizes phase information in two dimensions and is, thus, more robust than conventional one-dimensional methods. An additional reference scan is required which takes approximately 2 min for a matrix size of 64/spl times/64 and a repetition time of 2 s. Results from a water phantom and a human brain at 3 T demonstrate the effectiveness of the method for removing ghosts and geometric distortion artifacts.

A longitudinal functional magnetic resonance imaging study of language development in children 5 to 11 years old

Language skills continue to develop rapidly in children during the school‐age years, and the “snapshot” view of the neural substrates of language provided by current neuroimaging studies cannot capture the dynamic changes associated with brain development. The aim of this study was to conduct a 5‐year longitudinal investigation of language development using functional magnetic resonance imaging in healthy children.

Developmental differences in white matter architecture between boys and girls

Previous studies have found developmental differences between males and females in brain structure. During childhood and adolescence, relative white matter volume increases faster in boys than in girls. Sex differences in the development of white matter microstructure were investigated in a cohort of normal children ages 5–18 in a cross‐sectional diffusion tensor imaging (DTI) study. Greater fractional anisotropy (FA) in boys was shown in associative white matter regions (including the frontal lobes), while greater FA in girls was shown in the splenium of the corpus callosum. Greater mean diffusivity (MD) in boys was shown in the corticospinal tract and in frontal white matter in the right hemisphere; greater MD in girls was shown in occipito‐parietal regions and the most superior aspect of the corticospinal tract in the right hemisphere. Significant sex–age interactions on FA and MD were also shown. Girls displayed a greater rate of fiber density increase with age when compared with boys in associative regions (reflected in MD values). However, girls displayed a trend toward increased organization with age (reflected in FA values) only in the right hemisphere, while boys displayed this trend only in the left hemisphere. These results indicate differing developmental trajectories in white matter for boys and girls and the importance of taking sex into account in developmental DTI studies. The results also may have implications for the study of the relationship of brain architecture with intelligence. Hum Brain Mapp, 2008.

Differences in white matter architecture between musicians and non-musicians: a diffusion tensor imaging study.

Previous studies found structural brain differences between musicians and non-musicians. In order to determine possible differences in white matter architecture, diffusion tensor imaging was performed on five adult subjects with musical training since early childhood, and seven adult controls. The musicians displayed significantly greater fractional anisotropy (FA) in the genu of the corpus callosum, while significantly less FA was found in the corona radiata and the internal capsule bilaterally. Further areas also showed significant differences. We hypothesize that these changes are due to the cognitive and motor effects, respectively, of musical training.

A combined bootstrap/histogram analysis approach for computing a lateralization index from neuroimaging data

Cerebral hemispheric specialization has traditionally been described using a lateralization index (LI). Such an index, however, shows a very severe threshold dependency and is prone to be influenced by statistical outliers. Reliability of this index thus has been inherently weak, and the assessment of this reliability is as yet not possible as methods to detect such outliers are not available. Here, we propose a new approach to calculating a lateralization index on functional magnetic resonance imaging data by combining a bootstrap procedure with a histogram analysis approach. Synthetic and real functional magnetic resonance imaging data was used to assess performance of our approach. Using a bootstrap algorithm, 10,000 indices are iteratively calculated at different thresholds, yielding a robust mean, maximum and minimum LI and thus allowing to attach a confidence interval to a given index. Taking thresholds into account, an overall weighted bootstrapped lateralization index is calculated. Additional histogram analyses of these bootstrapped values allow to judge reliability and the influence of outliers within the data. We conclude that the proposed methods yield a robust and specific lateralization index, sensitively detect outliers and allow to assess the underlying data quality.