Mapping progressive loss of gray matter during early-onset schizophrenia

Schizophrenia typically has its onset in late adolescence or early adulthood, but cases that occur in childhood or early adolescence appear to be clinically and neurobiologically similar to later-onset illness. Early-onset schizophrenia may offer special opportunities to study how the disease develops and may help to discover its causes. For this reason, a team of neuroscientists (Thompson et al., 2001) used MRI to map, over a five-year period, the brains of 12 patients, 6 male and 6 female, with childhood-onset schizophrenia (COS), and a parallel group of 12 healthy adolescents. A third group of subjects were controls for medication; these were 10 non-schizophrenic adolescents who exhibited chronic mood disturbance and lack of behavioral control for which they were being treated with the same medications as the COS patients. MRI scans were first taken when the subjects were about 13.5 years old, then again about 2.5 years later, and finally about 5 years after the first scans.

Three-dimensional maps of brain changes were derived from the MRI scans. Several are presented in the report, color-coded to show different degrees of change, and one appears on the cover of the September 25, 2000 number of Proceedings of the National Academy of Sciences. Significant differences appeared between COS and non-schizophrenic adolescents, whether the latter were healthy or under medication. These differences appeared first in parietal cortex, areas which the investigators note are involved in visuospatial and associative thinking.

Over the five succeeding years, the cortical deficits of the COS patients progressed anteriorly into the sensorimotor and dorsolateral prefrontal cortex, the temporal lobe, and the frontal eye fields. The rate of increasing loss correlated with the severity of behavioral symptoms. The regions of loss corresponded with the impairments in neuromotor, auditory, visual search, and frontal executive functions that characterize schizophrenia. Thus this study confirms the loss of cortical volume in schizophrenic patients, a finding that earlier studies had left in doubt, as mentioned on p. 510. The loss of cortical tissue occurs in addition to the losses in structures that surround the cerebral ventricles, as reported on p. 509 and shown in Figures 16.3 and 16.4.

Some of the same investigators also participated in an MRI study of differences in cortical gray matter between monozygotic (MZ) twins discordant for schizophrenia (Cannon et al., 2001). As noted in Figure 16.1, the more closely related a person is to a patient with schizophrenia, the greater are his or her chances of also developing schizophrenia; nevertheless, only 48% of MZ twins of a person with schizophrenia also develop schizophrenia. The twin study was conducted with 5 male and 5 female pairs, averaging 48 years in age. The schizophrenic member of the pair showed statistically significant bilateral reductions of cortical thickness from 5 to 8% in dorsolateral prefrontal cortex and superior parietal cortex, and in the superior temporal gyrus of the left hemisphere. There were no significant differences between the discordant co-twins in primary sensory or motor areas. Since the MZ twins were identical genetically, the early loss of parietal cortex in the COS patients suggests an environmental rather than a genetic origin for the disease. In the frontal and temporal regions, however, where loss occurred relatively late in the COS patients, deficits in other familial studies appear to be highly heritable. Thus, although schizophrenia may be triggered by a nongenetic cause, the progress of the disease appears to have a heritable component. Further study of the development of brain changes in schizophrenia may help to elucidate these dynamics.

References:

Cannon, T.D., Thompson, P.M., van Erp, T., Toga, A.W. et al. (2001). A probabilistic atlas of cortical gray matter changes in monozygotic twins discordant for schizophrenia. 7th International Conference on Functional Mapping of the Human Brain, Brighton, England, June 2001.

Thompson, P.M., Vidal, C., Giedd, J.N., Gochman, P. et al. (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, 98:20, 11650-11655.