Vince Schmithorst

Normal fMRI Brain Activation Patterns in Children Performing a Verb Generation Task

Although much is known concerning brain-language relations in adults, little is known about how these functions might be represented during the developmental period. We report results from 17 normal children, ages 7-18 years, who have successfully completed a word fluency paradigm during functional magnetic resonance imaging at 3 Tesla. Regions of activation replicate those reported for adult subjects. However, a statistically significant association between hemispheric lateralization of activation and age was found in the children. Specifically, although most subjects at all ages showed left hemisphere dominance for this task, the degree of lateralization increased with age. This study demonstrates that fMRI can reveal developmental shifts in the pattern of brain activation associated with semantic language function.

Altered cellular dynamics and endosteal location of aged early hematopoietic progenitor cells revealed by time-lapse intravital imaging in long bones

Aged hematopoietic stem cells (HSCs) are impaired in supporting hematopoiesis. The molecular and cellular mechanisms of stem cell aging are not well defined. HSCs interact with nonhematopoietic stroma cells in the bone marrow forming the niche. Interactions of hematopoietic cells with the stroma/microenvironment inside bone cavities are central to hematopoiesis as they regulate cell proliferation, self-renewal, and differentiation. We recently hypothesized that one underlying cause of altered hematopoiesis in aging might be due to altered interactions of aged stem cells with the microenvironment/niche. We developed time-lapse 2-photon microscopy and novel image analysis algorithms to quantify the dynamics of young and aged hematopoietic cells inside the marrow of long bones of mice in vivo. We report in this study that aged early hematopoietic progenitor cells (eHPCs) present with increased cell protrusion movement in vivo and localize more distantly to the endosteum compared with young eHPCs. This correlated with reduced adhesion to stroma cells as well as reduced cell polarity upon adhesion of aged eHPCs. These data support a role of altered eHPC dynamics and altered cell polarity, and thus altered niche biology in mechanisms of mammalian aging.

Practical aspects of conducting large-scale functional magnetic resonance imaging studies in children

The potential benefits of functional magnetic resonance imaging (MRI) for the investigation of normal development have been limited by difficulties in its use with children. We describe the practical aspects, including failure rates, involved in conducting large-scale functional MRI studies with normal children. Two hundred and nine healthy children between the ages of 5 and 18 years participated in a functional MRI study of language development. Reliable activation maps were obtained across the age range. Younger children had significantly higher failure rates than older children and adolescents. It is concluded that it is feasible to conduct large-scale functional MRI studies of children as young as 5 years old. These findings can be used by other research groups to guide study design and plans for recruitment of young subjects. (J Child Neurol 2002;17:885—889).

Sex differences in the activation of language cortex during childhood.

Sex differences have been well documented in the behavioral literature but have occurred inconsistently in the neuroimaging literature. This investigation examined the impact of subject age, language task, and cortical region on the occurrence of sex differences in functional magnetic resonance imaging. Two hundred and five (104 m, 101 f) right handed, monolingual English speaking children between the ages of 5 and 18 years were enrolled in this study. The study used fMRI at 3T to evaluate BOLD signal variation associated with sex, age, and their interaction. Children completed up to four language tasks, which involved listening to stories, prosody processing, single word vocabulary identification, and verb generation. A sex difference for behavioral performance was found for the prosodic processing task only. Brain activation in the classical left hemisphere language areas of the brain and their right homologues were assessed for sex differences. Although left lateralization was present for both frontal and temporal regions for all but the prosody task, no significant sex differences were found for the degree of lateralization. Sex x age interaction effects were found for all but the task involving single word vocabulary. However effect sizes associated with the sex differences were small, which suggests that relatively large sample sizes would be needed to detect these effects reliably.

BOLD-fMRI signal increases with age in selected brain regions in children

To determine whether the BOLD signal used in fMRI is age dependent in childhood, 332 healthy children (age 4.9–18.9 years) performed tasks in a periodic block design during 3 T fMRI: (1) a verb generation task interleaved with a finger tapping task; (2) a word-picture matching task interleaved with an image discrimination task. Significant correlations between percent signal change in BOLD effect and age occurred in left Brocas, middle frontal, Wernickes, and inferior parietal regions, and anterior cingulate during the verb generation task; in precentral, postcentral, middle frontal, supplementary motor, and precuneus regions during the finger tapping task; and in bilateral lingula gyri during the word-picture matching task. Thus, BOLD effect increases with age in children during sensorimotor and language tasks.

Cortical Reorganization of Language Functioning Following Perinatal Left MCA Stroke

OBJECTIVE Functional MRI was used to determine differences in patterns of cortical activation between children who suffered perinatal left middle cerebral artery (MCA) stroke and healthy children performing a silent verb generation task. METHODS Ten children with prior perinatal left MCA stroke (age 6-16 years) and ten healthy age matched controls completed an executive language activation task. fMRI scans were acquired on a 3T scanner using T2* weighted gradient echo, echo-planar imaging (EPI) sequence. Random effects analysis and independent component analysis (ICA) were used to compute activation maps. RESULTS Both analysis methods demonstrated alternative activation of cortical areas in children with perinatal stroke. Following perinatal stroke, typical left dominant productive language areas in the inferior frontal gyrus were displaced to anatomical identical areas in the right hemisphere (p=.001). In addition, stroke patients showed more bilateral activation in superior temporal and anterior cingulate gyri and increased activation in primary visual cortex when compared to healthy controls. There was no relation between lesion size and the degree of right hemisphere activation. ICA showed that the healthy controls had a negative correlation with the time course in the right inferior frontal gyrus in the same region that was activated in stroke subjects. INTERPRETATION This functional MRI study in children revealed novel patterns of cortical language reorganization following perinatal stroke. The addition of ICA is complementary to Random Effects Analysis, allowing for the exploration of potential subtle differences in pathways in functional MRI data obtained from both healthy and pathological groups.

Prosodic Processing by Children: An fMRI Study.

Prosodic information in the speech signal carries information about linguistic structure as well as emotional content. Although children are known to use prosodic information from infancy onward to assist linguistic decoding, the brain correlates of this skill in childhood have not yet been the subject of study. Brain activation associated with processing of linguistic prosody was examined in a study of 284 normally developing children between the ages of 5 and 18 years. Children listened to low-pass filtered sentences and were asked to detect those that matched a target sentence. fMRI scanning revealed multiple regions of activation that predicted behavioral performance, independent of age-related changes in activation. Likewise, age-related changes in task activation were found that were independent of differences in task accuracy. The overall pattern of activation is interpreted in light of task demands and factors that may underlie age-related changes in task performance.

Regional vulnerability of longitudinal cortical association connectivity: Associated with structural network topology alterations in preterm children with cerebral palsy

Preterm born children with spastic diplegia type of cerebral palsy and white matter injury or periventricular leukomalacia (PVL), are known to have motor, visual and cognitive impairments. Most diffusion tensor imaging (DTI) studies performed in this group have demonstrated widespread abnormalities using averaged deterministic tractography and voxel-based DTI measurements. Little is known about structural network correlates of white matter topography and reorganization in preterm cerebral palsy, despite the availability of new therapies and the need for brain imaging biomarkers. Here, we combined novel post-processing methodology of probabilistic tractography data in this preterm cohort to improve spatial and regional delineation of longitudinal cortical association tract abnormalities using an along-tract approach, and compared these data to structural DTI cortical network topology analysis. DTI images were acquired on 16 preterm children with cerebral palsy (mean age 5.6 ± 4) and 75 healthy controls (mean age 5.7 ± 3.4). Despite mean tract analysis, Tract-Based Spatial Statistics (TBSS) and voxel-based morphometry (VBM) demonstrating diffusely reduced fractional anisotropy (FA) reduction in all white matter tracts, the along-tract analysis improved the detection of regional tract vulnerability. The along-tract map-structural network topology correlates revealed two associations: (1) reduced regional posterior–anterior gradient in FA of the longitudinal visual cortical association tracts (inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, optic radiation, posterior thalamic radiation) correlated with reduced posterior–anterior gradient of intra-regional (nodal efficiency) metrics with relative sparing of frontal and temporal regions; and (2) reduced regional FA within frontal–thalamic–striatal white matter pathways (anterior limb/anterior thalamic radiation, superior longitudinal fasciculus and cortical spinal tract) correlated with alteration in eigenvector centrality, clustering coefficient (inter-regional) and participation co-efficient (inter-modular) alterations of frontal–striatal and fronto-limbic nodes suggesting re-organization of these pathways. Both along tract and structural topology network measurements correlated strongly with motor and visual clinical outcome scores. This study shows the value of combining along-tract analysis and structural network topology in depicting not only selective parietal occipital regional vulnerability but also reorganization of frontal–striatal and frontal–limbic pathways in preterm children with cerebral palsy. These finding also support the concept that widespread, but selective posterior–anterior neural network connectivity alterations in preterm children with cerebral palsy likely contribute to the pathogenesis of neurosensory and cognitive impairment in this group.

Reprint of “Cortical reorganization of language functioning following perinatal left MCA stroke” [Brain and Language 105 (2008) 99–111]

OBJECTIVE Functional MRI was used to determine differences in patterns of cortical activation between children who suffered perinatal left middle cerebral artery (MCA) stroke and healthy children performing a silent verb generation task. METHODS Ten children with prior perinatal left MCA stroke (age 6-16 years) and ten healthy age matched controls completed an executive language activation task. fMRI scans were acquired on a 3T scanner using T2* weighted gradient echo, echo-planar imaging (EPI) sequence. Random effects analysis and independent component analysis (ICA) were used to compute activation maps. RESULTS Both analysis methods demonstrated alternative activation of cortical areas in children with perinatal stroke. Following perinatal stroke, typical left dominant productive language areas in the inferior frontal gyrus were displaced to anatomical identical areas in the right hemisphere (p=.001). In addition, stroke patients showed more bilateral activation in superior temporal and anterior cingulate gyri and increased activation in primary visual cortex when compared to healthy controls. There was no relation between lesion size and the degree of right hemisphere activation. ICA showed that the healthy controls had a negative correlation with the time course in the right inferior frontal gyrus in the same region that was activated in stroke subjects. INTERPRETATION This functional MRI study in children revealed novel patterns of cortical language reorganization following perinatal stroke. The addition of ICA is complementary to Random Effects Analysis, allowing for the exploration of potential subtle differences in pathways in functional MRI data obtained from both healthy and pathological groups.