Reduced Functional Brain Activation and Connectivity During a Working Memory Task in Childhood-Onset Schizophrenia

Abstract

Objective: Working memory (WM) deficits are consistently reported in schizophrenia and are related to poor functional outcomes. Functional magnetic resonance imaging studies of adult-onset schizophrenia have reported decreased functional activations and connectivity in the WM network, but no prior functional magnetic resonance imaging study has examined WM in childhood-onset schizophrenia (COS). The aim of this study was to examine the neural correlates of WM in COS.

Method: Adult patients with COS (n = 32, 21.3 ± 1.1 years), nonpsychotic siblings of patients with COS (n = 30, 19.4 ± 0.8 years), and healthy controls (n = 39, 20.0 ± 0.7 years) completed 1- and 2-back WM tasks during 3-T functional magnetic resonance imaging. Functional activation and connectivity analyses were conducted. A separate group of 23 younger patients with COS (17.9 ± 7.4 years) could not perform the tasks after twice completing a standard training and are not included in this report.

Results: Patients with COS who were included scored significantly lower than controls on all tasks (p < .001). Patients with COS showed significantly lower activations in the dorsolateral prefrontal cortices, posterior parietal cortices, cerebellum, and caudate and decreased frontoparietal and corticostriatal functional connectivity compared with controls (p < .05, corrected). Siblings had functional activations and connectivity intermediate between those of patients and controls in a similar set of regions (p < .05, corrected). In patients, functional connectivity strength in the left frontoparietal network correlated positively with accuracy scores during the 1-back task (p = .0023, corrected).

Conclusion: Decreased functional activation and connectivity in the WM network in COS supports pathophysiologic continuity with adult-onset schizophrenia. The low participation rate and accuracy of the patients highlights the disease severity of COS. Hypo-activations and hypo-connectivity were shared by siblings of patients with COS, suggesting COS as a potential endophenotype.

Clinical trial registration information: Evaluating Genetic Risk Factors for Childhood-Onset Schizophrenia; http://ClinicalTrials.gov;NCT00001198.

Keywords: childhood-onset schizophrenia; functional magnetic resonance imaging; working memory.

Published by Elsevier Inc.

Figures

Figure 1

Decreased functional activation in patients and siblings compared to controls during 1- and 2-back tasks. Note: Colored Z-scores indicate co-occurring significant brain activations during both 1- and 2-back tasks versus 0-back task. A typical working memory (WM)-related activation pattern was found in patients with childhood-onset schizophrenia (COS), their siblings, and healthy controls as shown in the union activation map of these three groups (A). Within these activated regions, both patients (B) and siblings (C) showed reduced activations compared with controls. In addition, patients showed lower activations than their siblings (D). All clusters are significant (p < .05, corrected), and co-occurring maps were generated by minimum Z conjunction of 1- and 2-back contrasts. Montreal Neurological Institute coordinates of peak regions in (B), (C), and (D) are listed in Table S2, available online.

Figure 2

Decreased functional connectivity in patients compared to controls and siblings. Note: Patients showed significantly lower functional connectivity between seeds in the left column and many of brain regions on the right (that were activated, shown in Figure 1A) than controls during 1-back (A) and siblings during 1-back (C) and 2-back (D). In addition, siblings also showed lower functional connectivity than controls (B). Seeds were defined by regions showing lower activations in patients or siblings compared with controls (see details in Figure S6, available online). All clusters are significant (p < .05, corrected for both the number of voxels and seeds examined). LPP = lateral posterior parietal cortex.

Figure 3

Correlation between task performance and functional connectivity in patients with children-onset schizophrenia. Note: Functional connectivity between the left lateral posterior parietal (LPP) and the left dorsal lateral prefrontal cortex (DLPFC, see the second row of Figure 2 for its group difference) correlated positively with accuracy scores of patients during 1-back task, Spearman correlation r = 0.53, p=.0023 < .05/12=.0042, Bonferroni correction of a total of twelve examined pairs of seed and target areas (in Figure 2A).