Deborah Waber - US grants

Survival rates for children with acute lymphoblastic leukemia (ALL) have been improved dramatically in the last decade. A major contributing feature of successful therapy was the introduction of central nervous system (CNS) prophylaxis (intrathecal methotrexate and cranial irradiation). However, many long-term survivors have now been found to exhibit cognitive deficits. This impairment is generally attributed to damage sustained by the developing nervous system in the course of treatment. The child's age at the time of treatment is apparently a critical factor. Existing studies suggest that children who are younger when treated exhibit more severe deficits. The proposed study is a detailed examination of the relationship of CNS impairment to the age at which CNS prophylaxis is administered. Specifically, we shall determine how the severity and nature of impairment are related to treatment age, the role of time elapsed since treatment, and the role of experimental factors related to life-threatening illness in childhood. A retrospective study is planned in which approximately 100 long-term survivors will receive a detailed neurological and neuropsychological evaluation. This study will provide a detailed assessment of the sequelae of CNS prophylaxis. Its findings will be of considerable value in evaluating the relative risks and benefits of treatment as well as in providing adequate counseling and treatment for the increasing number of long-term survivors who are now presenting with significant cognitive and behavioral difficulties. In addition, the study provides a unique opportunity to gain insight into normal and abnormal processes of human CNS development in the early years of life.

Project III tests the general hypothesis that patterns of low-level information processing will be systematically associated with clinical manifestations of learning disorders. We will determine whether interindividual differences among LD children, based on patterns of performance on measures of low level information processing (LLIP), are systematically associated with clinical test performance. Learning disabled children (N = 200) will be examined on standard and clinical profile measures of neurodevelopmental status and neuropsychological function, as well as on measures of oral and written language and mathematics competence. LLIP profiles, as ascertained in Project I, will be examined for their association with specific features of the clinical presentation. A secondary aim is to determine whether neurobehavioral profiles, as ascertained by neurological and neuropsychological assessment, are associated with each other and with characteristic pattern of academic expression.

Although there is a vast research literature on learning disabilities (LD), experts cannot agree on answers to the questions asked most frequently by parents and teachers, namely, does the child have a learning disability and, if so, what is the problem and what can be done about it. A fundamental premise of the proposed Center is that LD is a disorder of neurodevelopment, not a disorder of specific skill acquisition. Questions to be addressed by the research program are: what neurodevelopmental characteristics can reliably distinguish LD children from non-LD children and what characteristics distinguish these children from one another. The central hypothesis to be tested is that rapid processing of temporal information is specifically disordered in LD children. We will evaluate various aspects of low-level information processing by means of coordinated studies of auditory, visual and motor behavioral paradigms, quantitative EEG and functional MRI in order to elucidate the fundamental "building blocks" of central nervous system function that are associated with LD. These will be examined in relation to the higher order features of cognition, academic performance, and social adaptation that are of greatest clinical concern. The Center comprises three Cores (Administrative, Neurobehavioral Assessment, and Human Subjects and Data Management/Biostatistics) and five projects. ,All are focussed on a single cohort of LD children, and each addresses a different level of neurobehavioral analysis. The study sample will include LD children between the ages of 8 and 11 years (N = 200) and a standardization sample of same age children (N=200). Goals of the program include (1) to determine to what extent LD children can be differentiated from a normative sample by characteristics of their low level information processing; (2) to evaluate the reliability and validity of low level information processing "signatures" of LD; (3) to define the neural "building blocks" that are associated with LD. It is anticipated that a more thorough understanding of these "building blocks" will provide a basis for novel approaches to the treatment of this disorder.