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May 24, 2004 to May 26, 2004
Bethesda, Maryland

Introduction

The purpose of this conference?co-sponsored by the National Institutes of Health?s National Institute of Child Health & Human Development (NICHD), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Biomedical Imaging and Bioengineering (NIBIB)?was to foster translational research involving pediatric functional brain development using functional neuroimaging, which focused on both normal brain development and developmental deviations across a variety of disorders. This exchange opened up opportunities for coordinated efforts involving comparison of disorders and ages across sites. Speakers at this conference concentrated on design and analysis issues for pediatric development studies, domains and key paradigms with high clinical relevance, advances in fMRI and integration of imaging across modalities, and data sharing. A selection of the presentations made at this meeting appear below.

fMRI of Normal Language Development in Children

Scott K. Holland, Ph.D.

Dr. Scott Holland discussed his ongoing 5-year functional magnetic resonance imaging (fMRI) study of normal language development in children ages 5 to 18. The study began in 1998 when attempts to investigate the localization of language acquisition to one side of the brain (lateralization) in epileptic children revealed a dearth of information. Dr. Holland first created reference standards for brain activity during language acquisition in normal children. While being scanned, participants performed language tasks designed to contrast vocabulary-processing skills (lexicality) with the ability to form sentences (sentential skills). Finger-tapping tasks were performed as a nonlanguage control task.

Holland’s study population included: (1) a normally developing group of boys and girls at each year of age from 5 to 18; (2) a longitudinal group of 20 children who entered the study at age 7; and (3) 10 children who experienced severe perinatal strokes.

He presented composite brain activation maps and lateralization growth curves for each of the fMRI language tasks and animations showing the evolution of language activation patterns that change as a function of age. These changes closely followed hypotheses about the developmental skill levels required for each task and its content. Results demonstrated that semantic (relating to meaning) and syntactic (rules governing how words are put together to form sentences) skills and the brain areas involved with them continue to develop throughout the age span.

Lastly, preliminary findings in children with severe left hemisphere damage in the language areas were compared with normative composite data. fMRI revealed lateralization variations in brains of epileptic children as a function of age. Differences have also been revealed in brain activation during language tasks in children who had experienced perinatal stroke. Holland concluded that fMRI could also be a valuable tool for following subtle changes in less severe pathologies, such as lead exposure.

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Development of Cognitive and Neural Processes Underlying Conflict Resolution

B.J. Casey, Ph.D.

Dr. B.J. Casey reviewed her model of cognitive control (executive function), as well as the behavioral and imaging studies that have examined the neural processes underlying its development. An essential component of executive function is the ability to predict when events will occur, which is critical for planning and maintaining appropriate thoughts and actions. When these expectations are violated, one must employ a form of detection that triggers adjustments in behavior (cognitive control) to override inappropriate thoughts and actions. This ability continues to develop throughout childhood, but is disrupted by a number of childhood disorders, including childhood-onset schizophrenia, attention deficit hyperactivity disorder (ADHD), and substance abuse.

Casey and her colleagues used fMRI and diffusion tensor brain imaging (DTI) to map connectivity of frontostriatal, frontoamygdala, and frontocerebellar neural circuits involved in the development of cognitive processing and control. Subjects completed a battery of tasks, which required inhibition of a stimulus, inhibition of a behavior, and complete inhibition of a response. Some tasks attempted to elicit appropriate responses after presentation of cognitive information that violates expectations. Images of activated brain areas were captured, then correlated with behavior.

Significant differences were noted between adults and children. Task accuracy increased and reaction time decreased on stimulus selection tasks as normally developing children approached puberty, and adult levels of accuracy were reached by adolescence. Schizophrenic subjects had difficulty suppressing irrelevant but salient stimuli during the stimulus selection tasks, while children with ADHD showed deficits on both the stimulus selection and response execution tasks. Lastly, adolescents demonstrated enhanced activation when presented with unexpected stimuli.

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Brain Imaging Studies of Developmentally Based Psychopathologies

Bradley S. Peterson, M.D.

In his presentation, Dr. Bradley Peterson summarized and provided examples of the conceptual, methodological, and statistical challenges of using neuroimaging to understand developmentally based psychopathologies. He explained that an individual’s adaptation to debilitating symptoms will likely alter broadly distributed brain systems, thus making it difficult to distinguish adaptive changes from the pathological processes that induced the compensatory changes. The challenge, according to Peterson, is to distinguish findings that represent core pathophysiology from epiphenomena (arising as a result of the illness) and from findings arising from adaptive changes.

Similarly, delineating the natural history and developmental correlates of an illness is also challenging. Researchers often assume that cross-sectional studies belong to a larger general population of individuals with the same biological disease, presuming that younger subjects will eventually resemble older counterparts. Peterson cautioned that this assumption is often false, and that most childhood-onset illnesses differ from their adult counterparts in associated comorbidities, degree of familial risk, and other factors.

Peterson concluded by suggesting that ensuing imaging studies of developmentally based psychopathologies move from convenient sample groups in temporal cross-section to representative samples using novel and more informative experimental designs. He also recommended that (1) progressively younger age groups and high-risk cohorts be included in future studies; (2) imaging studies be linked with clinical trials so that the causally relevant variable under study can be experimentally controlled and manipulated; and (3) fMRI studies include basic elementary tasks that differ minimally across groups in performance and processing strategies to better define origins and timing of differences when they first appear.

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Mapping Cortical Development Using Diffusion Tensor Imaging

Jeffrey J. Neil, M.D., Ph.D.

Diffusion tensor imaging (DTI) is a method of magnetic resonance imaging that measures water diffusion across several tissue axes, thus providing information regarding microstructure. It is useful for brain imaging because water displacements are not the same throughout the brain. In white matter, displacements are smaller, or more restricted than and perpendicular to myelinated fibers as they create physical boundaries that slow the diffusion of water molecules. This restricted diffusion is "anisotropic." Brain injury of any kind instantly causes a reduction in water displacement and diffusion coefficients making DTI an excellent diagnostic tool for early detection of brain injury and the occurrence of stroke. In this presentation, Dr. Jeffrey Neil detailed the specific principles of DTI, and gave examples of its use by several researchers and clinicians in studies of brain injury, normal brain morphology, and developing human and baboon brains.

In brain development studies, cortical grey matter in adult human subjects shows low values for diffusion anisotropy. However, early in development, the cortex shows very strong anisotropy. This has also has been observed in DTI studies of the developing baboon brain. These observations may represent more prominent laminar brain organization and less radial organization during brain development; however, more work needs to be done in human infants at various stages of development to confirm this. DTI is even useful with fixed tissue. Although there is less diffusion in fixed tissue, anisotropy and directional correlations are identical to those in the living human brain.

Neil concluded that the advent of DTI will allow the development of white matter fiber tracking algorithms and provide a rapid, noninvasive exam to better study and document white matter changes in cognitive processes. The use of DTI to measure and monitor cognitive and motor performances opens a new vista in the field of neuroimaging for early intervention and remediation of neural dysfunction.

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Pediatric Applications of MRS

Stephen R. Dager, M.D.

Magnetic resonance spectroscopy (MRS) can detect and quantify various brain tissue-based chemicals and brain levels of certain psychotropic medications increasingly being prescribed to pediatric populations. Dr. Stephen Dager explained the usefulness of MRS in the noninvasive investigation of brain pharmacokinetics, including measurement of brain uptake, steady-state, brain binding and brain half-life, and for the study of pediatric neuropsychiatric disorders, such as factors that underlie abnormal brain maturation processes in autism. MRS is an ideal modality for use with pediatric populations, as it is noninvasive, does not involve ionizing radiation and, for some applications such as studying brain pharmakokinetics, is less sensitive to movement than other magnetic resonance techniques.

Dager’s group used MRS to investigate the brain pharmacokinetics of selective serotonin re-uptake inhibitors (SSRIs) prescribed to pediatric patients being treated for pervasive developmental disorders. Data were compared to similar data from adults prescribed the same drugs. A significant relationship was shown between dose and drug concentration in the brain for fluvoxamine or fluoxetine across the age range studied. It was concluded that a reasonable target dose range for prescribing these drugs in pediatric populations could be determined by scaling adult doses in relationship to body mass.

Dager also covered results from an ongoing longitudinal MRS imaging study of preschool-aged children with autism spectrum disorder (ASD). Regional brain chemistry was evaluated for evidence of increased neuronal packing density or decreased synaptic pruning, postulated by some as an explanation for manifestations of autism. In the context of characteristic brain structural abnormalities, Dager found brain chemical abnormalities that were detectable in autistic children at 3–4 years of age, but the findings do not support hypotheses of diffuse increased neuronal packing density in ASD.

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The NIH MRI Study of Normal Brain Development

Alan C. Evans, Ph.D.

Little data on normal brain function and development exists to compare with data from patients with neuropsychiatric disorders. Such norms are also lacking for brain imaging studies, leading to noncomparable findings and excessive duplication in scanning control subjects. NIDA, NIMH, NICHD, and NINDS are co-sponsoring a $28 million initiative using aMRI (anatomic magnetic resonance imaging), DTI, and MRS to create the world's first large-scale database on normal brain development in children. This initiative is the NIH MRI Study of Normal Brain Development.

Dr. Alan Evans explained that the study is working with seven major research centers to scan the brains of more than 500 infants, children, and adolescents, and catalog normal structural development by age and sex. Children ages 5 and older will receive additional scans and clinical and behavioral reassessments at 2-year intervals. Younger children are being re-scanned more frequently—at 3- to 12-month intervals—to capture more rapid brain maturation changes occurring at these ages.

Evans discussed how the study will chart normal growth curves of brain structures, revealing the development of circuitry for language, thinking, and other functions and allowing scientists a much more detailed view of developmental changes. By comparing scans of children with neuropsychiatric disorders with this normative data, researchers will be able to determine the timing and developmental course of brain structure changes in childhood disorders. Imaging and extensive clinical/behavioral data are being transferred to a database that will ultimately facilitate early diagnosis and differentiation of various disorders, and speed up the development of targeted treatments and evaluations of their effects.

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