Working memory and DLPFC inefficiency in schizophrenia: the FBIRN study

Abstract

Background: The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory.

Methods: In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads.

Results: Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics.

Conclusions: The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency.

Fig. 1.

Time Course of the SIRP Design.

Fig. 2.

Image of the DLPFC Mask Shown in Standard MNI Space.

Fig. 3.

Mean Accuracy at Each Memory Load by Diagnostic Group. (a) Mean accuracy levels in the entire 217 subject dataset. Error bars equal 1 SD. (b) Mean accuracy levels in the behaviorally matched subsample (65 SZ, 65 HV). Error bars indicate 1 SD.

Fig. 4.

The Mean Time Courses of Activation Averaged Across All Voxels Within the Left (a, c) and Right (b, d) Hemisphere DLPFC Regions of Interest for Healthy Controls (a, b) and Schizophrenic (c, d) Subjects. The horizontal axis represents time in seconds relative to the onset of the memorandum at time zero (0) for memory loads of 1 (blue line), 3 (red line), and 5 (green line) items. The first memory probe was presented at 7 sec and the last memory probe occurred at 38 sec.

Fig. 5.

BOLD Signal Change in DLPFC, by Load and Hemisphere, for HV and Schizophrenic Patients. (a) Encode results by diagnostic group. (b) Probe results by diagnostic group. Error bars indicate one standard deviation.

Fig. 6.

As in figure 5 but limited to the behaviorally matched sample.