The identification of markers for the prediction of psychosis is central to the development of early intervention and prevention strategies for schizophrenia. Primary or secondary prevention strategies oriented to the pre-psychosis and pre-prodromal periods have not been attempted because of an absence of biomarkers or solid knowledge of pathophysiology in the period before adolescence prior to the emergence of mild psychotic symptoms (i.e., prior to the putative "prodrome"). Because there is consistent evidence of significant neuropsychological and social deficits beginning in early childhood of people who later develop schizophrenia, there is strong reason to believe that brain abnormalities are present in the preteen years, but there is no evidence as yet about such abnormalities in that period. The present proposal aims to begin to fill that critical gap of knowledge. Indeed, some of the earliest symptoms of schizophrenia such as disturbances in the sense of self, and those that reflect impaired metacognition such as impaired self-other boundaries are frequently present in those at risk for schizophrenia (ARS) in the age range we intend to study. We hypothesize that the neurobiology of the "early premorbid" period, is characterized by brain dysmaturation, reflected in altered cortical thickness, volume reduction in hippocampus and medial prefrontal cortex, abnormal information processing and dysfunctional connectivity. This preliminary study, focused on children at risk for schizophrenia, ages 8- 11, is designed to test hypotheses about brain function, structure, and cognition in a cross-sectional design that will lay a foundation for subsequent grants designed to study the longitudinal evolution of brain structure and function in prepubertal ARS children. This project will focus on a novel, but highly promising area of new research;the neural substrates of the inner experience of the child at risk, by evaluating (using functional MRI): 1). the "default mode" of brain function and;2). the neural network underlying 'self reflection'(reflection about oneself or others). Moreover, we will extend to childhood our previous work in adolescents demonstrating;3). altered brain function during working memory and 4). structural abnormalities. The study goals are consistent with the R21 guidelines emphasizing novelty and innovation, in regard to the feasibility of conducting these imaging studies in young children. Moreover, the study is consistent with the 2008 NIMH Strategic Plan in which prediction and prevention of schizophrenia and disability in those at risk for the illness are key NIH priorities.

Public Health Relevance

This preliminary study, focused on children at risk for schizophrenia, ages 8-11, is designed to begin to fill a critical gap of knowledge regarding brain function and structure in the pre-teen period. The identification of markers for the prediction of psychosis is central to the development of early intervention and prevention strategies for schizophrenia. Primary prevention strategies oriented to the pre-psychosis and pre-prodromal periods have not been attempted because of an absence of biomarkers or solid knowledge of pathophysiology in the period before adolescence prior to the emergence of mild psychotic symptoms (i.e., putative "prodrome"). The information gathered from the project is of significant public health relevance, in that it will characterize the neural and cognitive capacities of the pre-teen child who is at familial risk for schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH092840-01A1
Application #
8241537
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Friedman-Hill, Stacia
Project Start
2012-02-15
Project End
2013-12-31
Budget Start
2012-02-15
Budget End
2012-12-31
Support Year
1
Fiscal Year
2012
Total Cost
$276,018
Indirect Cost
$83,651
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Thermenos, H W; Keshavan, M S; Juelich, R J et al. (2013) A review of neuroimaging studies of young relatives of individuals with schizophrenia: a developmental perspective from schizotaxia to schizophrenia. Am J Med Genet B Neuropsychiatr Genet 162B:604-35
Brent, Benjamin K; Thermenos, Heidi W; Keshavan, Matcheri S et al. (2013) Gray matter alterations in schizophrenia high-risk youth and early-onset schizophrenia: a review of structural MRI findings. Child Adolesc Psychiatr Clin N Am 22:689-714
Walder, Deborah J; Holtzman, Carrie W; Addington, Jean et al. (2013) Sexual dimorphisms and prediction of conversion in the NAPLS psychosis prodrome. Schizophr Res 144:43-50