Genes influence the amplitude and timing of brain hemodynamic responses.

In functional magnetic resonance imaging (fMRI), the hemodynamic response function (HRF) reflects regulation of regional cerebral blood flow in response to neuronal activation. The HRF varies significantly between individuals. This study investigated the genetic contribution to individual variation in HRF using fMRI data from 125 monozygotic (MZ) and 149 dizygotic (DZ) twin pairs. The resemblance in amplitude, latency, and duration of the HRF in six regions in the frontal and parietal lobes was compared between MZ and DZ twin pairs. Heritability was estimated using an ACE (Additive genetic, Common environmental, and unique Environmental factors) model. The genetic influence on the temporal profile and amplitude of HRF was moderate to strong (24%-51%). The HRF may be used in the genetic analysis of diseases with a cerebrovascular etiology.

Cerebral glucose metabolism on positron emission tomography of children.

Establishing the normative range of age-dependent fluorodeoxyglucose (FDG) uptake in the developing brain is necessary for understanding regional quantitative analysis of positron emission tomography (PET) brain images in children and also to provide functional information on brain development. We analyzed head sections of FDG PET/computed tomography (CT) images for 115 patients (5 months to 23 years) without central nervous system disease before treatment, as PET studies are not performed on healthy children owing to ethical considerations and the risk of radiation exposure. We investigated the changes in FDG uptake and established age-associated normative ranges of cerebral FDG. Head sections of FDG PET/CT images were registered to a population-based probabilistic atlas of human cortical structures. Gray matter of 56 brain structures was defined on normalized PET images according to the atlas. To avoid individual and experimental confounding factors, the relative standardized uptake value (SUV) over the cerebellum of each structure was calculated. Relative SUVs were analyzed by ANOVA and modeled using generalized estimating equalization analysis with false discovery rate control. Age and structure were significant factors affecting SUVs. Anatomic proximity had little effect on FDG uptake. Linear and quadratic developmental trajectories were observed on absolute and relative SUVs, respectively. An increase from posterior-to-anterior and superior-to-inferior pattern was observed in both absolute SUV increase rate and relative SUV peak age. The SUV of each structure was modeled with respect to age, and these models can serve as baselines for the quantitative analysis of cerebral FDG-PET images of children.

Mapping developmental precentral and postcentral gyral changes in children on magnetic resonance images.

PURPOSE: To study the shape changes in precentral gyrus (PRG) and postcentral gyrus (PCG) during healthy brain development in childhood. MATERIALS AND METHODS: Magnetic resonance (MR) images from 20 healthy children scanned twice at 6.3 ± 0.8 and 8.1 ± 0.9 years old were analyzed in this study. The analysis steps included: 1) The PRG and PCG were manually segmented from the MR images of each subject; 2) 3D mesh representing the PRG and PCG were built from the manually segmented images; 3) a series of shape description features were extracted and statistically analyzed by a permutation test method. RESULTS: This study showed the following statistically significant findings (P < 0.05): left PCG and PRG are located more posteriorly and superiorly than their right compartments; the hemispheric asymmetry of the PRG in the inferior-superior direction decreased after 2 years; the superior part of the PCG and PRG shifted and rotated to the posterior side of the brain. CONCLUSION: During normal pediatric brain development hemispheric asymmetry and shape of PCG and PRG are changed. These findings, together with previous reports in the literature, illustrate a region-specific brain structure maturation pattern in children and may be related to changing neurocognitive functions.

Retrospective evaluation of PET-MRI registration algorithms.

The purpose of this study is to evaluate the accuracy of registration positron emission tomography (PET) head images to the MRI-based brain atlas. The [(18)F]fluoro-2-deoxyglucose PET images were normalized to the MRI-based brain atlas using nine registration algorithms including objective functions of ratio image uniformity (RIU), normalized mutual information (NMI), and normalized cross correlation (CC) and transformation models of rigid-body, linear, affine, and nonlinear transformations. The accuracy of normalization was evaluated by visual inspection and quantified by the gray matter (GM) concordance between normalized PET images and the brain atlas. The linear and affine registration based on the RIU provided the best GM concordance (average similarity index of 0.71 for both). We also observed that the GM concordances of linear and affine registration were higher than those of the rigid and nonlinear registration among the methods evaluated.

Quantitative morphologic evaluation of white matter in survivors of childhood medulloblastoma.

In survivors of pediatric brain tumors, cranial radiation therapy can cause a debilitating cognitive decline associated with decreased volume in normal-appearing white matter (NAWM). We applied fractal geometry to quantify white matter (WM) integrity in the brain of medulloblastoma survivors. Fractal features of WM were evaluated by indices of fractal dimensions (FDs) of WM intensity and boundary on T1-weighted magnetic resonance images. The FD index of WM intensity was calculated by using a fractional Brownian motion model, and the FD index of WM boundary was calculated by using a box-counting method. Fractal features of WM on 116 magnetic resonance images of 58 patients with medulloblastoma were investigated at the start of therapy (Start TX) and approximately 2 years later (After TX). Patients were assigned to one of two groups based on change in NAWM volumes. Fractal features in patients with decreased NAWM volume were significantly greater After TX, whereas those in patients with increased NAWM volumes were not. Multiple linear regression analysis showed that fractal features were strongly correlated with NAWM volumes After TX in patients with decreased NAWM volume. These results demonstrated significant deficit in NAWM integrity and WM density changes in children treated for medulloblastoma. Multiple regression analysis illustrated that deficits in NAWM integrity in these children may partly explain the decrease in NAWM volume. We conclude that fractal geometry can be used to monitor the morphologic effects of neurotoxicity in brain tumor survivors.

MRI changes and complement activation correlate with epileptogenicity in a mouse model of temporal lobe epilepsy.

The complex pathogenesis of temporal lobe epilepsy includes neuronal and glial pathology, synaptic reorganization, and an immune response. However, the spatio-temporal pattern of structural changes in the brain that provide a substrate for seizure generation and modulate the seizure phenotype is yet to be completely elucidated. We used quantitative magnetic resonance imaging (MRI) to study structural changes triggered by status epilepticus (SE) and their association with epileptogenesis and with activation of complement component 3 (C3). SE was induced by injection of pilocarpine in CD1 mice. Quantitative diffusion-weighted imaging and T2 relaxometry was performed using a 16.4-Tesla MRI scanner at 3 h and 1, 2, 7, 14, 28, 35, and 49 days post-SE. Following longitudinal MRI examinations, spontaneous recurrent seizures and interictal spikes were quantified using continuous video-EEG monitoring. Immunohistochemical analysis of C3 expression was performed at 48 h, 7 days, and 4 months post-SE. MRI changes were dynamic, reflecting different outcomes in relation to the development of epilepsy. Apparent diffusion coefficient changes in the hippocampus at 7 days post-SE correlated with the severity of the evolving epilepsy. C3 activation was found in all stages of epileptogenesis within the areas with significant MRI changes and correlated with the severity of epileptic condition.

Modeling of the hemodynamic responses in block design fMRI studies.

The hemodynamic response function (HRF) describes the local response of brain vasculature to functional activation. Accurate HRF modeling enables the investigation of cerebral blood flow regulation and improves our ability to interpret fMRI results. Block designs have been used extensively as fMRI paradigms because detection power is maximized; however, block designs are not optimal for HRF parameter estimation. Here we assessed the utility of block design fMRI data for HRF modeling. The trueness (relative deviation), precision (relative uncertainty), and identifiability (goodness-of-fit) of different HRF models were examined and test-retest reproducibility of HRF parameter estimates was assessed using computer simulations and fMRI data from 82 healthy young adult twins acquired on two occasions 3 to 4 months apart. The effects of systematically varying attributes of the block design paradigm were also examined. In our comparison of five HRF models, the model comprising the sum of two gamma functions with six free parameters had greatest parameter accuracy and identifiability. Hemodynamic response function height and time to peak were highly reproducible between studies and width was moderately reproducible but the reproducibility of onset time was low. This study established the feasibility and test-retest reliability of estimating HRF parameters using data from block design fMRI studies.

A knowledge-guided active model method of cortical structure segmentation on pediatric MR images.

PURPOSE: To develop an automated method for quantification of cortical structures on pediatric MR images. MATERIALS AND METHODS: A knowledge-guided active model (KAM) approach was proposed with a novel object function similar to the Gibbs free energy function. Triangular mesh models were transformed to images of a given subject by maximizing entropy, and then actively slithered to boundaries of structures by minimizing enthalpy. Volumetric results and image similarities of 10 different cortical structures segmented by KAM were compared with those traced manually. Furthermore, the segmentation performances of KAM and SPM2, (statistical parametric mapping, a MATLAB software package) were compared. RESULTS: The averaged volumetric agreements between KAM- and manually-defined structures (both 0.95 for structures in healthy children and children with medulloblastoma) were higher than the volumetric agreement for SPM2 (0.90 and 0.80, respectively). The similarity measurements (kappa) between KAM- and manually-defined structures (0.95 and 0.93, respectively) were higher than those for SPM2 (both 0.86). CONCLUSION: We have developed a novel automatic algorithm, KAM, for segmentation of cortical structures on MR images of pediatric patients. Our preliminary results indicated that when segmenting cortical structures, KAM was in better agreement with manually-delineated structures than SPM2. KAM can potentially be used to segment cortical structures for conformal radiation therapy planning and for quantitative evaluation of changes in disease or abnormality.

A digital pediatric brain structure atlas from T1-weighted MR images.

Human brain atlases are indispensable tools in model-based segmentation and quantitative analysis of brain structures. However, adult brain atlases do not adequately represent the normal maturational patterns of the pediatric brain, and the use of an adult model in pediatric studies may introduce substantial bias. Therefore, we proposed to develop a digital atlas of the pediatric human brain in this study. The atlas was constructed from T1-weighted MR data set of a 9-year old, right-handed girl. Furthermore, we extracted and simplified boundary surfaces of 25 manually defined brain structures (cortical and subcortical) based on surface curvature. We constructed a 3D triangular mesh model for each structure by triangulation of the structure's reference points. Kappa statistics (cortical, 0.97; subcortical, 0.91) indicated substantial similarities between the mesh-defined and the original volumes. Our brain atlas and structural mesh models (www.stjude.org/brainatlas) can be used to plan treatment, to conduct knowledge and model-driven segmentation, and to analyze the shapes of brain structures in pediatric patients.

Smaller white-matter volumes are associated with larger deficits in attention and learning among long-term survivors of acute lymphoblastic leukemia.

BACKGROUND: The primary objective of this study was to test the hypothesis that survivors of childhood acute lymphoblastic leukemia (ALL) have deficits in neurocognitive performance, and smaller white-matter volumes are associated with these deficits. METHODS: The patients studied included 112 ALL survivors (84 patients who had received chemotherapy only, 28 patients who had received chemotherapy and irradiation; 63 males, 49 females; mean age +/- standard deviation, 4.1 yrs +/- 2.6 yrs at diagnosis; mean +/- standard deviation yrs since diagnosis, 6.0 +/- 3.5 yrs), and 33 healthy siblings who participated as a control group. Neurocognitive tests of attention, intelligence, and academic achievement were performed; and magnetic resonance images were obtained and subsequently were segmented to yield tissue volume measurements. Comparisons of neurocognitive measures and tissue volumes between groups were performed, and the correlations between volumes and neurocognitive performance measures were assessed. RESULTS: Most performance measures demonstrated statistically significant differences from the normative test scores, but only attention measures exceeded 1.0 standard deviation from normal. Patients who had received chemotherapy alone had significantly larger volumes of white matter than patients who had received treatment that also included cranial irradiation, but their volumes remained significantly smaller than the volumes in the control group. Smaller white-matter volumes were associated significantly with larger deficits in attention, intelligence, and academic achievement. CONCLUSIONS: Survivors of childhood ALL had significant deficits in attention and smaller white-matter volumes that were associated directly with impaired neurocognitive performance. Cranial irradiation exacerbated these deficits.