1Paul M. Thompson,
1Christine N. Vidal,
2Jay N. Giedd,
3Tyrone D. Cannon,
1Arthur W. Toga,
2Judith L. Rapoport
1Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, UCLA School of Medicine, Los Angeles, CA
2Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD
3Department of Psychology and Human Genetics, UCLA School of Medicine, Los Angeles, CA
Objective: We review recent developments in brain imaging that have identified new features of normal and abnormal development. We focus on efforts by our group and others to relate patterns of tissue growth and loss in childhood and adolescence to clinical, cognitive and genetic parameters. Specifically, we describe an image analysis approach we developed to map brain changes in the NIMH childhood-onset schizophrenia (COS) cohort. These patients, as well as temporally yoked and medication-matched controls, were imaged longitudinally with MRI over a 5-year time span. In COS, waves of cortical gray matter loss spread through the brain during adolescence. These were linked with clinical measures (CGAS), cognitive performance, and psychotic symptom severity (SANS/SAPS scores). We also review novel approaches to map genetic influences on brain structure. These can (1) isolate brain changes induced by non-genetic factors; (2) identify deficit patterns mediated by genetic factors, and map them in genetically at-risk relatives; (3) test linkages between candidate genes and brain structure deficits.
Conclusion: Brain imaging provides a powerful tool to identify complex brain changes in normal and abnormal development. Dynamic and genetic brain maps, in particular, show promise in revealing how genes and environment interact to induce these brain changes.
The talk will cover three main areas related to normal and abnormal development. We will briefly review recent findings, focusing on recent advances made possible by brain imaging studies, and current challenges. The following topics will be covered:
1. Mapping Normal Development. Although volumes of brain substructures are known to change during development, detailed maps of these dynamic growth processes have been unavailable. We will describe the creation of spatially complex, four-dimensional quantitative maps of growth patterns in the developing human brain, detected using a ‘tensor mapping’ strategy . This approach maps growth patterns in greater spatial detail and sensitivity than previously obtainable. By repeatedly scanning children (aged 3-15 years) across time spans of up to four years, a rostro-caudal wave of growth was detected at the corpus callosum. During the ages 3-6 years, fastest growth occurred in circuits innervating the frontal cortices. From age 6 until puberty, peak growth rates were found in the callosal isthmus, in fibers innervating perisylvian association and language cortices. At the same time a severe, spatially localized loss of gray matter occurred in the basal ganglia. We describe how local rates, profiles, and principal directions of growth can be visualized in individual children, and how these maps can shed light on healthy and abnormal development.
2. Mapping Abnormal Development: Recent Findings in Childhood-Onset Schizophrenia.
We also describe how recent imaging studies have been used to understand brain changes that occur in childhood-onset schizophrenia (COS). Using novel brain mapping algorithms, we detected striking anatomical profiles of accelerated gray matter loss in COS ; surprisingly, deficits moved in a dynamic pattern enveloping increasing amounts of cortex throughout adolescence. Early-onset patients were re-scanned prospectively with MRI, at two-year intervals at three time-points, to uncover the dynamics and timing of disease progression during adolescence. The earliest deficits were found in parietal brain regions, supporting visuo-spatial and associative thinking, where adult deficits are known to be mediated by environmental (nongenetic) factors. Over 5 years, these deficits progressed anteriorly into temporal lobes, engulfing sensorimotor and dorsolateral pre-frontal cortices, and frontal eye fields. These emerging patterns correlated with psychotic symptom severity, and mirrored the neuromotor, auditory, visual search and frontal executive impairments in the disease. In temporal regions, gray matter loss was completely absent early in the disease but became pervasive later. Only the latest changes included dorsolateral prefrontal cortex and superior temporal gyri, deficit regions found consistently in adult studies. These emerging dynamic patterns were (1) controlled for medication and IQ effects, (2) replicated in independent groups of males and females, and (3) charted in individuals and groups. The resulting mapping strategy reveals a shifting pattern of tissue loss in schizophrenia.
3. Genetic Brain Maps. Finally, we describe some more recent imaging studies that have used twin designs to help understand genetic influences in brain development and disease. We highlight two studies as illustrative examples, one using new mathematical/computational strategies to map how genes influence normal brain structure , and one using a discordance design  to map genetic influences on brain structure in schizophrenia. We will describe how novel aspects of the anatomy and dynamics of disease are uncovered, in a changing profile that implicates genetic and non-genetic patterns of deficits.
Conclusion. Brain imaging provides a powerful tool to identify complex brain changes in normal and abnormal development. Dynamic [1,2] and genetic [3,4] brain maps, as described in this talk, show enormous promise in revealing how genes and environment interact to induce these changes.
. Thompson PM, Giedd JN, Woods RP, MacDonald D, Evans AC, Toga AW (2000). Growth Patterns in the Developing Brain Detected By Using Continuum-Mechanical Tensor Maps, Nature, 404:(6774) 190-193, March 9, 2000.
. Thompson PM, Vidal CN, Giedd JN, Gochman P, Blumenthal J, Nicolson R, Toga AW, Rapoport JL (2001). Mapping Adolescent Brain Change Reveals Dynamic Wave of Accelerated Gray Matter Loss in Very Early-Onset Schizophrenia, Proceedings of the National Academy of Sciences of the USA, 98(20):11650-11655, September 25, 2001.
. Thompson PM, Cannon TD, Narr KL, van Erp T, Khaledy M, Poutanen V-P, Huttunen M, Lönnqvist J, Standertskjöld-Nordenstam C-G, Kaprio J, Dail R, Zoumalan CI, Toga AW (2001). Genetic Influences on Brain Structure, Nature Neuroscience 4(12):1253-8, Dec. 2001.
. Cannon TD, Thompson PM, van Erp T, Toga AW, Poutanen V-P, Huttunen M, Lönnqvist J, Standertskjöld-Nordenstam C-G, Narr KL, Khaledy M, Zoumalan CI, Dail R, Kaprio J (2002). Cortex Mapping Reveals Regionally-Specific Pattern of Genetic and Disease-Specific Gray Matter Deficits in Twins Discordant for Schizophrenia, Proceedings of the National Academy of Sciences of the USA, [in press].
. Sowell ER, Thompson PM, Holmes CJ, Jernigan TL, Toga AW (1999). Progression of Structural Changes in the Human Brain during the First Three Decades of Life: In Vivo Evidence for Post-Adolescent Frontal and Striatal Maturation, Nature Neuroscience 2(10):859-61, October 1999.
Paul Thompson, Ph.D.
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