Cortical brain development in schizophrenia: insights from neuroimaging studies in childhood-onset schizophrenia

Abstract

Childhood-onset schizophrenia (COS; defined as onset by age 12 years) is rare, difficult to diagnose, and represents a severe and chronic phenotype of the adult-onset illness. A study of childhood-onset psychoses has been ongoing at the National Institute of Mental Health (NIMH) since 1990, where children with COS and severe atypical psychoses (provisionally labeled "multidimensionally impaired" or MDI by the NIMH team) are studied prospectively along with all first-degree relatives. COS subjects have robust cortical gray matter (GM) loss during adolescence, which appears to be an exaggeration of the normal cortical GM developmental pattern and eventually mimics the pattern seen in adult-onset cases as the children become young adults. These cortical GM changes in COS are diagnostically specific and seemingly unrelated to the effects of medications. Furthermore, the cortical GM loss is also shared by healthy full siblings of COS probands suggesting a genetic influence on the abnormal brain development.

Fig. 1.

Comparison of the Patterns of Cortical Gray Matter (GM) Loss in Childhood-Onset Schizophrenia (COS) (Between Ages 12 and 16 Years) to That Seen in Normal Cortical Maturation (Between Ages 4 and 22 Years). A. Right lateral view of the dynamic sequences of cortical GM maturation in healthy children between ages 4 and 22 years (n = 13, 54 scans, upper panel) rescanned every 2 years. Scale bar shows GM amount at each of the 65 536 cortical points across the entire cortex represented using a color scale (red to pink—more GM, blue—GM Loss). Cortical GM maturation appears to progress in a “back-to-front” (parietotemporal) manner. B. Right lateral view of the dynamic sequence of cortical GM maturation in COS between ages 12 and 16 years compared with age- and sex-matched healthy controls (n = 12, 36 scans in each group), where children are rescanned every 2 years. Dynamic maps represent P values for the difference in GM amount between COS and controls at each of the 65 536 cortical points, and P values are represented using a color scale (eg, pink, P < .00002). Cortical GM loss in COS also appears to follow in a “back-to-front” direction on the lateral surface, thus suggesting that the COS pattern is an exaggeration of the normal GM maturation. Asterisk represents data on childhood schizophrenia only age 12–16 years. Adapted from Proc Natl Acad Sci USA 2004;101:8178 and Proc Natl Acad Sci USA 2001;98:11652.

Fig. 2.

Progression of Cortical Gray Matter (GM) Loss in Childhood-Onset Schizophrenia (COS) (n = 70, 162 scans) Relative to Age-, Sex-, and Scan Interval–Matched Healthy Controls (n = 72, 168 Scans) From Adolescence to Young Adulthood (age 12–24 years). Analyses were done using mixed model regression statistics and covaried from mean cortical thickness. Side bar shows t statistic with threshold to control for multiple comparisons using the false discovery rate procedure with q = 0.05. Differences are from mixed model regression with age centered at approximate 3-year intervals for middle 80% of the age range, and colors represent areas of statistically significant thinning in COS. Adapted from Child Psychol Psychiatry 2006;47:1007.

Fig. 3.

Cortical Gray Matter (GM) Thickness in Healthy Childhood-Onset Schizophrenia (COS) Siblings (n = 52, 110 scans) Compared With Age-, Sex-, and Scan Interval–Matched Healthy Controls (n = 52, 108 scans) Between Ages 8 Through 28 Years. Healthy COS siblings show significant GM deficits in left prefrontal and bilateral temporal cortices and smaller deficits in right prefrontal and inferior parietal cortices. These deficits in healthy siblings normalize with age with no abnormalities remaining by age 20 years. Side bar shows t statistic with threshold to control for multiple comparisons using the false discovery rate procedure with q = 0.05. Differences are from mixed model regression with age centered at approximate 3-year intervals for middle 80% of the age range, and colors represent areas of statistically significant thinning in COS siblings. Adapted from Arch Gen Psychiatry. 2007;64:774.