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Brain Imaging Links Motor, Cognitive Deficits in Schizophrenia

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.

Finding correlations
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.

Reference:
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

Comments on News and Primary Papers
Comment by:  Daniel Weinberger, SRF Advisor
Submitted 26 October 2006
Posted 26 October 2006
  I recommend the Primary Papers

This paper by Ridler and colleagues is an interesting novel twist on other evidence that developmental milestones, even in traditionally hard wired motor functions, are slightly delayed in samples of individuals who later manifest schizophrenia. There are two important additional results that emerge from their analysis: first, that early developmental motor milestones predict MRI measures of brain volume and executive function during adulthood in normal individuals; and second, that these predictive relationships are not found in their schizophrenia sample.

The link between early motor and adult cognitive development is not surprising, as child development studies have highlighted the predictive implications of precocious motor development for cognitive development. The link to volumetric measures on MRI is intriguing and novel, though as in all MRI volumetry studies, the tissue compartments that contribute to variance in the MRI measures are uncertain. I doubt that MRI volume measures are sensitive assessments of variation in synaptic abundance or other elements related to synaptic plasticity. So, the biologic basis for this correlation is intriguing but uncertain.

Finally, the finding of no relationship between these measures in schizophrenia might reflect a deviation in development of the neural systems involved the patients, as the authors suggest, but it might also argue that there is a confounder in the schizophrenia results that obscures the relationships found in the normal subjects. One possibility is medication, which can affect cognitive measures and MRI measures.

View all comments by Daniel WeinbergerComment by:  Patricia Estani
Submitted 2 November 2006
Posted 2 November 2006
  I recommend the Primary Papers

Comments on Related News


Related News: Channels of Working Memory

Comment by:  David C. Glahn
Submitted 11 March 2014
Posted 11 March 2014

The article by Heck and colleagues provides additional support for the notion that common genetic factors influence risk for schizophrenia and working memory performance. While evidence that working memory performance is sensitive to genetic liability for schizophrenia was well established by twin and family studies (e.g., Cannon et al., 2000; Glahn et al., 2007), the current article extends these findings by suggesting that at least a portion of this joint effect is conferred by common variants in the voltage-gated cation channel activity (see QuickGO page) gene network. The paper provides a potential biological mechanism through which a set of genes could influence both traits. Such testable biological hypotheses are critical both for unraveling the genetic architecture of schizophrenia and other psychotic illnesses and for helping to characterize how these genes aid in manifesting the behavioral disorders. Thus, although the paper does not provide a single pleiotropic gene as would be required in classical human genetics, I believe the findings represent a true advancement in our understanding of schizophrenia genetics.

A major strength of the paper is the large number of independent samples with similar, but not identical, working memory measures that provided data for the discovery or replication samples. Papassotiropoulos and his group have applied this powerful approach to provide insight into the genetic make-up of cognitive processes, particularly memory.

Recently, there has been a good deal of debate concerning the utility of endophenotypes in the search for mental illness genes. As described by Gottesman and Gould (Gottesman and Gould, 2003), endophenotypes are measurable components unseen by the unaided eye along the pathway between disease and distal genotype. John Blangero and I pointed out that joint genetic determination (pleiotropy) of endophenotype and disease risk is fundamental to the endophenotype concept (Glahn et al., 2012). The current paper clearly demonstrates pleiotropy between schizophrenia risk and working memory performance, reinforcing working memory as a schizophrenia endophenotype and demonstrating how such traits can be used to provide testable biological hypotheses.

Finally, I would like to point out that this work was primarily conducted in healthy individuals not selected for mental illness. The endophenotype and normal variation strategy (e.g., using unselected samples to learn about the genetic factors influencing an endophenotype and then confirming these results in a sample selected for the illness) has worked in other areas of medicine, and I believe it will work in psychiatric genetics as well. Indeed, I think this paper demonstrated exactly that.

References:

Cannon TD, Huttunen MO, Lonnqvist J, Tuulio-Henriksson A, Pirkola T, Glahn D, Finkelstein J, Hietanen M, Kaprio J, Koskenvuo M. The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet. 2000 Aug;67(2):369-82. Epub 2000 Jul 3. Abstract

Glahn DC, Almasy L, Blangero J, Burk GM, Estrada J, Peralta JM, Meyenberg N, Castro MP, Barrett J, Nicolini H, Raventós H, Escamilla MA. Adjudicating neurocognitive endophenotypes for schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2007 Mar 5;144B(2):242-9. Abstract

Glahn DC, Curran JE, Winkler AM, Carless MA, Kent JW Jr, Charlesworth JC, Johnson MP, Göring HH, Cole SA, Dyer TD, Moses EK, Olvera RL, Kochunov P, Duggirala R, Fox PT, Almasy L, Blangero J. High dimensional endophenotype ranking in the search for major depression risk genes. Biol Psychiatry. 2012 Jan 1;71(1):6-14. Abstract

Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003 Apr;160(4):636-45. Review. Abstract

View all comments by David C. Glahn