22 October 2006. Children who will later develop schizophrenia are more likely to show subtle movement deficits: for example, learning to walk a little later than their peers. As adults, after the disorder has appeared, they perform worse on tests of certain cognitive domains. A new study suggests that these seemingly disparate deficits can be traced to the same brain systems.
In the study, Peter Jones, Edward Bullmore, and colleagues at the University of Cambridge in the UK, with collaborators at the University of Oulu, Finland, combined prospectively gathered data on infant motor development with executive function tests and structural MRI imaging conducted when the study subjects were adults. Writing in PNAS, they report that normal individuals who stand and walk early will, on average, have better performance on cognitive tests of adult executive function. Furthermore, both early motor development and better adult executive function are associated with more grey and white matter in some of the same frontal cortical and cerebellar regions. However, in people with schizophrenia, these correlations break down: earlier motor development and better adult executive function are not associated with these cortical or cerebellar structural differences. Therefore, according to lead author Khanum Ridler and colleagues, the study suggests disruption of these systems might underlie the childhood developmental abnormalities and adult cognitive abnormalities of schizophrenia.
Aberrant early brain development
It is widely accepted in the schizophrenia research field that schizophrenia is a delayed consequence of aberrant early brain development (Weinberger, 1987; Murray and Lewis, 1987). Longitudinal epidemiological studies have shown that subtle abnormalities in social function and cognition during childhood often precede the emergence of psychotic symptoms in adult patients with schizophrenia. Interestingly, abnormalities of early motor development have also been found to be associated with an increased risk of schizophrenia. In adults, a motoric aspect of schizophrenia called extrapyramidal movement disorder tends to be present at first diagnosis before antipsychotic medications are begun.
To account for these observations, it has been suggested that a single brain system may be responsible for the acquisition of early motor skills as well as for aspects of later cognitive function, and that abnormality of this system increases the risk of schizophrenia (Gottesman and Gould, 2003). In separate work, other researchers have posited that the diverse profile of abnormalities seen in patients with schizophrenia can be explained by a “cognitive dysmetria” model in which there is an improper integration of fronto-cerebellar-thalamic circuits that prioritize, process, coordinate, and trigger responses to information (Andreasen et al., 1998).
Infant motor development, adult executive function, and brain structure data
Ridler and colleagues drew a study sample of 93 non-psychotic adults and 43 adults with schizophrenia from the Northern Finland 1966 Birth Cohort of 10,934 individuals. Non-psychotic volunteers were randomly selected from cohort members living in the city of Oulu who had no history of psychosis on the Finnish Hospital Discharge Register. Similarly, adult cohort members with schizophrenia were identified on the Finnish Hospital Discharge Register and confirmed via chart review. Of these patients, 72 percent were taking antipsychotic medications at the time of this study.
For infant motor development data, the authors surveyed the prospective assessments of age at learning to stand without support and to walk with and without support as recorded during children’s visits to welfare centers and during a special Birth Cohort examination at age 1 year. Of note, the authors state that missing data on age at learning to walk were entered as age at time of missing assessment plus 1 month. They did not mention how prevalent missing data were in this study.
Adult executive function testing and whole-brain MRI scanning were performed between 1999 and 2001, when the study subjects were 33-35 years old. When possible, executive function testing was performed on the same day as the MRI scan; if that was not possible, the test was performed within two weeks of the MRI scan. The executive function test used was the computer-based abstraction, inhibition, and working memory (AIM) task.
Ridler and colleagues first looked at the infant motor development data and confirmed earlier findings that the mean age at learning to stand and to walk was significantly delayed in patients with schizophrenia. Whereas those in the non-psychotic group had a mean age of learning to stand of 10.8 months, patients with schizophrenia had a mean age of learning to stand of 11.7 months (P <.002). The results were similar for age of walking with support (9.2 months vs. 10.3 months; P <.0001) and without support (11.9 months vs. 12.5 months; P <.009). As in previous studies, adult executive function was also compromised in patients with schizophrenia at a highly significant level (P <.001). Linking these two assessments, the authors found that precocious infant motor development was positively correlated with better adult executive function in non-psychotic adults. No significant correlation, however, was found between infant motor development and adult executive function in the patients with schizophrenia.
When examining the full-brain MRI scans of the non-psychotic subjects using computational morphometry, the investigators found that earlier infant motor development was significantly positively associated with a greater grey matter density in three areas: the bilateral and medial premotor cortex and the bilateral rostral prefrontal cortex; the left caudate nucleus (head and body) and left thalamus; and the medial cerebellum. Earlier infant motor development was also significantly positively associated with greater white matter volume and density in the frontal lobes, the left parietal lobe, and immediately adjacent to the left caudate nucleus and thalamus. No regions of grey or white matter density or volume were found to be associated with infant motor development in patients with schizophrenia, however.
The investigators also found associations between adult executive function scores and brain structure in non-psychotic subjects which did not carry over to patients with schizophrenia. Again using computational morphometry, Ridler and colleagues found a significant positive association between higher executive function scores and increased grey matter density in four regions: the bilateral medial premotor cortex and left rostral prefrontal cortex; the right inferior and middle frontal gyri; the bilateral medial cerebellum; and the right posterolateral cerebellum. None of these regions was associated with executive function in patients with schizophrenia.
The authors note that there is only partial overlap in the brain regions associated with infant motor development and in those associated with adult executive function. They write, “50 percent of the voxels in prefrontal/premotor cortex associated with adult executive function were also associated with infant motor development; likewise, 48 percent of the voxels in medial cerebellum associated with executive function were also associated with infant motor development.” They go on to suggest that it is “likely that adult executive systems emerge developmentally by integration of additional (prefrontal and lateral cerebellar) regions, with a ‘core’ or prototypic, frontal premotor-medial cerebellar circuit that has previously matured in support of early motor skills.”
In relating their findings to patients with schizophrenia, the researchers suggest that a possible early developmental failure in connectivity in the premotor cortex could lead to disruption in the fronto-cortico-cerebellar system that is critical for adult executive function. They write, “Disruption of this…system is a plausible endophenotype that may underlie both developmental and adult cognitive dysmetria in schizophrenia.”—Jillian Lokere.
Ridler K, Veijola JM, Tanskanen P, Miettunen J, Chitnis X, Suckling J, Murray GK, Haapea M, Jones PB, Isohanni MK, Bullmore ET. Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia. Proc Natl Acad Sci. 2006 Oct 6; [Epub ahead of print]. Abstract