Faculty Bibliography

In this study, we examined whether topologic network analysis, using resting state functional magnetic resonance imaging (MRI), can detect abnormalities of functional brain connectivity in children with unilateral brain injury due to Sturge-Weber syndrome. Three children with Sturge-Weber syndrome (ages 1, 3, and 10 years) underwent structural and resting state functional MRI, glucose metabolism positron emission tomography (PET), and neurocognitive evaluation. Eight different resting state networks were compared between the affected and unaffected hemispheres by quantitatively accessing communication efficiency measures. Significantly reduced efficiency values were found in all 3 patients. Visual network deficiency was present in both children with a visual field defect; frontal network abnormalities were associated with fine motor impairment. Location of network abnormalities corresponded to and, in some cases, extended beyond structural MRI and glucose PET abnormalities. The presented approach can detect early functional abnormalities of specific brain networks in children with Sturge-Weber syndrome.

PURPOSE/OBJECTIVE:Microstructural alterations seen in the epileptic cortex have been implicated as a cause and also result of multiple seizure activity. In the present study, we evaluated water diffusion changes at different cortical thickness fractions and in the underlying white matter of the epileptic cortex and compared them with electrographically normal cortex and also with corresponding cortical regions of healthy controls. METHODS:We selected 18 children with normal magnetic resonance imaging (MRI) who underwent two-stage epilepsy surgery to control seizures of neocortical origin, and compared their MR images with those of 18 age-matched healthy controls. First, delineation of the gray-white and gray-pial intersection surfaces was performed on high-resolution volumetric T1 MR images. Using the delineated surfaces as reference, diffusion values were measured at different cortical thickness fractions and in the underlying white matter at various depths, using diffusion tensor imaging (DTI). Cortical regions representing seizure onset and electrographically normal cortex were differentiated by electrocorticography in the epilepsy patients. KEY FINDINGS/RESULTS:We observed different patterns of diffusion abnormalities in both the seizure onset and electrographically normal cortical regions when compared to healthy controls. In the seizure-onset regions, a marked increase in diffusivity was noted in the cortical gray matter, and this increase was most pronounced in the outer fraction of the gray matter. Similarly, increased diffusivity was noted in the white matter underlying the epileptic cortex. The electrographically normal cortex, in contrast, showed decreased diffusivity in inner and middle cortical fractions compared to the controls. The white matter underlying the electrographically normal cortex did not show any difference in diffusivity between the children with epilepsy and controls. Finally, both the cortical gray matter and the underlying white matter regions showed decreased anisotropy in epileptic as well as electrographically normal regions when compared to controls. SIGNIFICANCE/CONCLUSIONS:Our results suggest specific patterns of diffusion changes in the cortical fractions and the underlying white matter of the epileptic region compared to electrographically normal and normal control regions. The abnormal increase in diffusivity of the superficial cortex might be associated with microstructural abnormalities commonly seen in layers II through IV of epileptic cortex. Such combined use of a high-resolution structural image to extract the laminar diffusion values, which are highly sensitive to microstructural alterations, could be of clinical value in localizing epileptogenic cortex.

PURPOSE/OBJECTIVE:To explore whether diffusion-weighted imaging (DWI) can localize specific segments of primary motor areas in children with Sturge-Weber syndrome (SWS), this study investigated the corticospinal tract (CST) between precentral gyrus (PCG) and posterior limb of internal capsule (PIC). MATERIALS AND METHODS/METHODS:DWI was performed on 32 healthy children and seven children with unilateral SWS affecting the sensorimotor area variably. A hierarchical dendrogram was applied to find PCG-segments uniquely connected to PIC-segments. The resulting PCG-clusters were used to image primary motor pathways in DWI and find metabolic abnormalities of primary motor areas in positron emission tomography (PET) scans. RESULTS:In healthy children, five PCG-clusters were found to have unique CST courses, corresponding to CST segments of mouth/lip, fingers, and leg/ankle primary motor areas determined by functional magnetic resonance imaging (fMRI). In children with SWS, reduced streamlines in these PCG clusters were highly correlated with glucose-hypometabolism on PET (R(2) = 0.2312, P = 0.0032). Impaired CST segment corresponding to finger movements correlated with severity of hand motor deficit. CONCLUSION/CONCLUSIONS:The presented method can detect impaired CST segments corresponding to specific motor functions in young children who cannot cooperate for fMRI. This approach can be clinically useful for a noninvasive presurgical evaluation of cortical motor areas in such children.

OBJECTIVE:We combined perfusion weighted imaging (PWI) with 2-deoxy-2[(18)F]fluoro-D-glucose (FDG) positron emission tomography (PET) to study the relationship between regional metabolic and perfusion abnormalities and their clinical correlates in children with Sturge-Weber syndrome (SWS). METHODS:Fifteen children (age: 0.9-10 years) with unilateral SWS underwent high-resolution PWI and FDG PET prospectively. Regional (lobar) asymmetry indices (AIs) of subcortical white matter (WM) cerebral blood flow (CBF) were correlated with corresponding cortical FDG uptake asymmetries, extent of leptomeningeal vascular malformation and clinical seizure variables. RESULTS:Abnormal cortical glucose metabolism and/or subcortical WM CBF were seen in all lobes affected by vascular malformation and extended to lobes not affected by abnormal pial vessels in 6 patients. Lower CBF was associated with lower cortical glucose metabolism in the temporal, parietal and occipital lobes (p≤0.02). While decreased perfusion was associated with hypometabolism in most cases, increased regional CBF (found in 6 patients) was commonly associated with relatively mild or no hypometabolism. Ten of 24 cerebral lobes with normal glucose metabolism in the affected hemisphere showed abnormal perfusion. High seizure frequency was associated with severe parieto-occipital hypoperfusion (p≤0.03), while long duration of epilepsy was related to frontal lobe hypometabolism (p=0.015). CONCLUSIONS:Regional perfusion and cortical metabolic abnormalities can extend beyond lobes affected by leptomeningeal vascular malformations and are related to epilepsy in SWS. Despite a general correlation between perfusion and metabolism, increased WM perfusion with preserved cortical metabolism in overlying cortex is a common pattern of a perfusion/metabolic mismatch. This may represent a disease stage where cortical function is preserved while increased WM perfusion provides collateral drainage of cortex via the deep vein system.

AIM/OBJECTIVE:In order to relate brain structural abnormalities to clinical features of Angelman Syndrome (AS), we determined the locations of abnormal regional white matter architecture in AS children using a sensitive and objective whole brain approach to analyze diffusion tensor imaging (DTI) color-coded orientation maps. METHODS:Using tract based spatial statistics (TBSS) of DTI color-coded orientation maps, the fraction of fibers oriented in the anteroposterior (AP), mediolateral (ML) and superioinferior (SI) directions were determined in whole brain white matter of 7 children with AS (mean age: 70±25.78 months, 5 males) and 7 children with typical development (TD, mean age: 79.8±17.25 months, 4 males). TBSS of FA map was also performed for comparison. RESULTS:Children with AS had a significantly lower AP component than the TD group in 9 clusters (3 bilateral and 3 unilateral). Bilateral clusters were located in inferior fronto-occipital fasciculus, anterior thalamic radiation and arcuate fasciculus regions. Unilateral clusters involved left brainstem, left cingulum and right uncinate regions. Similarly, children with AS had significantly lower ML component than the TD group in 4 clusters (2 in corpus callosum and 2 unilateral clusters). Unilateral clusters were located in the left cingulum and left anterior thalamic radiation regions. SI component was lower in children with AS in two clusters compared to TD (corticospinal tract and corpus callosum). FA map clusters mostly corresponded with component clusters. INTERPRETATION/CONCLUSIONS:Children with AS have a global impairment of white matter integrity including AP, ML and SI components in whole brain suggesting a potential underlying error with axon guidance mechanisms during brain development possibly due to loss of UBE3A gene expression. Some of this aberrant connectivity can be related to the clinical features of AS.

OBJECTIVE:To investigate whether abnormal regional white matter architecture in the perisylvian region could be used as an easy and sensitive quantitative method to demonstrate language pathway abnormalities in children with developmental delay (DD). STUDY DESIGN/METHODS:We performed diffusion tensor imaging in 15 DD subjects (age, 61.1 ± 20.9 months) and 15 age-matched typically developing (TD) children (age, 68.4 ± 19.2 months). With diffusion tensor imaging color-coded orientation maps, we quantified the fraction of fibers in the perisylvian region that are oriented in anteroposterior (AP) and mediolateral (ML) directions, and their ratio (AP/ML) was calculated. RESULTS:The AP/ML ratio was more sensitive than tractography in characterizing perisylvian regional abnormalities in DD children. The AP/ML ratio of the left perisylvian region was significantly lower in DD children compared with TD children (P = .03). The ML component of bilateral perisylvian regions was significantly higher in DD children compared with TD children (P = .01 [left] and P = .004 [right]). No significant difference was found in the AP component in the two groups. A significant negative correlation of the left ML component with Vineland communication skills was observed (r = -0.657, P = .011). CONCLUSIONS:The AP/ML ratio appears to be a sensitive indicator of regional white matter architectural abnormalities in the perisylvian region of DD children.

In comparison with other primate species, humans have an extended juvenile period during which the brain is more plastic. In the current study we sought to examine gene expression in the cerebral cortex during development in the context of this adaptive plasticity. We introduce an approach designed to discriminate genes with variable as opposed to uniform patterns of gene expression and found that greater inter-individual variance is observed among children than among adults. For the 337 transcripts that show this pattern, we found a significant overrepresentation of genes annotated to the immune system process (pFDR ~/= 0). Moreover, genes known to be important in neuronal function, such as brain-derived neurotrophic factor (BDNF), are included among the genes more variably expressed in childhood. We propose that the developmental period of heightened childhood neuronal plasticity is characterized by more dynamic patterns of gene expression in the cerebral cortex compared to adulthood when the brain is less plastic. That an overabundance of these genes are annotated to the immune system suggests that the functions of these genes can be thought of not only in the context of antigen processing and presentation, but also in the context of nervous system development.

BACKGROUND AND PURPOSE/OBJECTIVE:We used L-[1-(11) C]leucine (LEU) positron emission tomography (PET) to measure amino acid uptake in children with Sturge-Weber syndrome (SWS), and to relate amino acid uptake measures with glucose metabolism. METHODS:LEU and 2-deoxy-2[(18) F]fluoro-D-glucose (FDG) PET were performed in 7 children (age: 5 months-13 years) with unilateral SWS. Asymmetries of LEU uptake in the posterior brain region, underlying the angioma and in frontal cortex, were measured and correlated with glucose hypometabolism. Kinetic analysis of LEU uptake was performed in 4 patients. RESULTS:Increased LEU standard uptake value (SUV, mean: 15.1%) was found in the angioma region in 6 patients, and smaller increases in LEU SUV (11.5%) were seen in frontal cortex in 4 of the 6 patients, despite normal glucose metabolism in frontal regions. High LEU SUV was due to both increased tracer transport (3/4 patients) and high protein synthesis rates (2/4). FDG SUV asymmetries in the angioma region were inversely related to LEU SUV asymmetries (r=-.83, P= .042). CONCLUSIONS:Increased amino acid uptake in the angioma region and also in less affected frontal regions may provide a marker of pathological mechanisms contributing to chronic brain damage in children with SWS.

In this study, we determined whether diffusion tensor imaging (DTI), a more widely available imaging modality, is as effective as α-[(11)C]methyl-l-tryptophan (AMT)-positron emission tomography (PET) in localizing epileptogenic tubers in tuberous sclerosis complex. Following that, coregistration of AMT-PET and diffusion tensor imaging scans apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in all tubers using a region-of-interest approach and were compared with AMT-PET tuber/cortex uptake ratios, which were used to differentiate between epileptogenic and nonepileptogenic tubers. Forty-three tubers, out of a total of 320 tubers, had AMT-PET uptake ratios greater than 1 and hence were classified as potentially epileptogenic. FA in epileptogenic tubers was reduced compared with the other tubers (P = .03). A significant negative correlation was observed between AMT-PET uptake ratio of epileptogenic tubers and FA values (r = -.45; P = .003). Tubers with higher AMT-PET uptake ratios corresponded well with lower FA values in tuberous sclerosis complex patients.