White Matter Abnormalities in Early-Onset Schizophrenia: A Voxel-Based Diffusion Tensor Imaging Study SANJIV KUMRA, M.D., MANZAR ASHTARI, PH.D., KELLY L. CERVELLIONE, M.A., INIKA HENDERSON, PSY.D., HANA KESTER, B.A., DAVID ROOFEH, B.A., JINGHUI WU, B.S., TANA CLARKE, M.A., EMILY THADEN, B.A., JOHN M. KANE, M.D., JOSEPH RHINEWINE, PH.D., TODD LENCZ, PH.D., ALAN DIAMOND, M.D., BABAK A. ARDEKANI, PH.D., AND PHILIP R. SZESZKO, PH.D. ABSTRACT Objective: To investigate abnormalities in the structural integrity of brain white matter as suggested by diffusion tensor imaging in adolescents with early-onset schizophrenia (onset of psychosis by age 18). Method: Twenty-six patients with schizophrenia and 34 age- and gender-matched healthy volunteers received diffusion tensor imaging and structural mag- netic resonance imaging examinations. Fractional anisotropy maps were compared between groups in the white matter using a voxelwise analysis after intersubject registration to Talairach space. Results: Compared with healthy volunteers, patients demonstrated lower fractional anisotropy values in the left anterior cingulate region in close proximity to the cau- date nucleus (95% confidence interval of schizophrenic-healthy: –66 to –20). Using regression analysis, the rate of change in fractional anisotropy differed significantly between groups in this region across the age span examined (10–20 years), after adjusting for group differences in premorbid intellectual capacity and parental socioeconomic status. There were no areas of significantly higher fractional anisotropy in patients compared with healthy volunteers. Conclusions: These data suggest that early-onset schizophrenia is associated with a disruption in the structural integrity of white matter tracts in the anterior cingulate region. These structural abnormalities may contribute to the deficits in motivation, attention, memory, and higher executive functions in adolescents with schizophrenia. J. Am. Acad. Child Adolesc. Psychiatry, 2005;44(9): 934–941. Key Words: diffusion tensor imaging, schizophrenia, anterior cingulate, temporal lobes. The structural maturation of the frontal lobe and its connecting pathways are essential for the successful de- velopment of cognitive functions. As summarized by Sowell et al. (2003), converging data from electrophys- iological cerebral glucose metabolism, postmortem, an- imal, and structural magnetic resonance imaging (MRI) studies provide empirical evidence of ongoing matura- tion of the fiber projections to the frontal lobe during adolescence. Overall, these data suggest that the second decade of life may represent a particularly critical period in the structural maturation of fiber pathways connect- ing the frontal lobe to other brain regions. There is increasing evidence that the pathophysiology of schizophrenia involves a white matter component and that elements of white matter—myelin and oligo- dendroglia—are abnormal in frontal regions, creating a physiological obstacle with functional consequences to corticocortical and corticosubcortical interaction (Davis et al., 2003). In support of this model, the clin- ical presentation of patients with metachromatic leuko- dystrophy frequently includes psychotic symptoms, particularly when there is involvement of frontal subcortical white matter in the disease process and Accepted April 8, 2005. Drs. Kumra, Schvartz, Kane, Rhinewine, Lencz, and Szeszko, Ms. Cervellione, Ms. Kester, Mr. Roofeh, Ms. Wu, Ms. Clarke, and Ms. Thaden are with the De- partment of Psychiatry Research, The Zucker Hillside Hospital, North Shore–Long Island Jewish Health System, Glen Oaks, NY; Drs. Ashtari and Diamond are with the Department of Radiology, North Shore–Long Island Jewish Health System, New Hyde Park, NY; Dr. Ardekani is with Nathan S. Kline Institute for Psychi- atric Research, Center for Advanced Brain Imaging, Orangeburg, NY. This work was supported in part by grants from NARSAD (S.K. as a Lieber Investigator), The Whitaker Foundation (B.A., RG-00-0350), and the National Institute of Mental Health to Dr. Kumra (MH01990, MH60229, MH064556), Dr. Kane (MH60575, MH60004, MH41960), and Dr. Szeszko (MH401990). Correspondence to Dr. Sanjiv Kumra, Department of Psychiatry Research, The Zucker Hillside Hospital, North Shore–Long Island Jewish Health System, 75-59 263rd Street, Glen Oaks, NY 11004; e-mail: skumra@lij.edu. 0890-8567/05/4409–0934Ó2005 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000170553.15798.94 934 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 44:9, SEPTEMBER 2005