Disrupted Working Memory Circuitry in Schizophrenia: Disentangling fMRI Markers of Core Pathology vs Other Aspects of Impaired Performance

Abstract

Working memory (WM) impairment, a core feature of schizophrenia, is often associated with aberrant dorsolateral prefrontal cortex (dlPFC) activation. Reduced resting-state connectivity within the frontoparietal control network (FPCN) has also been reported in schizophrenia. However, interpretation of WM-related dlPFC dysfunction has been limited by performance differences between patients and controls, and by uncertainty over the relevance of resting-state connectivity to network engagement during task. We contrasted brain activation in 40 schizophrenia patients and 40 controls during verbal WM performance, and evaluated underlying functional connectivity during rest and task. During correct trials, patients demonstrated normal FPCN activation, despite an inverse relationship between positive symptoms and activation. FPCN activation differed between the groups only during error trials (controls>patients). In contrast, controls demonstrated stronger deactivation of the ventromedial prefrontal cortex (vmPFC) during correct and error trials. Functional connectivity analysis indicated impaired resting-state FPCN connectivity in patients, but normal connectivity during task. However, patients showed abnormal connectivity among regions such as vmPFC, lateral orbitofrontal cortex, and parahippocampal gyrus (PHG) during both rest and task. During task, patients also exhibited altered thalamic connectivity to PHG and FPCN. Activation and connectivity patterns that were more characteristic of controls generally correlated with better performance. In summary, patients demonstrated normal FPCN activation when they remained on-task, and exhibited normal FPCN connectivity during WM, whereas vmPFC deactivation differences persisted regardless of WM performance. Our findings suggest that altered FPCN activation in patients reflects performance difference, and that limbic and thalamic dysfunction is critically involved in WM deficits in schizophrenia.

Figure 1

Illustration of Sternberg Item Recognition Paradigm (SIRP). Each block started with presentation of the memorized set, which consisted of 1, 3, 5, or 7 letters. Then, single letters were presented in succession. Subjects' task was to press ‘1' on the keypad if the letter was a foil (not a letter in the memorized set), and to press ‘2' if it was a target. Subjects completed three 7-min runs in the scanner, each of which consisted of 112 trials.

Figure 2

Brain regions showing parametric activation in response to increasing task load during correct and error epochs. Each surface map is represented by four images with lateral and medial views on the left and right hemisphere. Maps for both control (left) and patient (middle) groups are shown together with group difference maps (right). Left lateral view of the group difference map for Correct vs Fix was tilted 20° for a better view of the postcentral gyrus. Both controls and patients demonstrated load-dependent activation in FPCN and deactivation in the DMN during correct epochs. Deactivation in mPFC was stronger in controls during both conditions. During error epochs, activation in the right dlPFC, SMG, and MTG was selectively stronger in controls. Colorbar denotes the p-value. All clusters displayed on maps survive correction for multiple comparisons using 10 000 Monte Carlo simulations at clusterwise p<0.05.

Figure 3

Differences in functional connectivity between the groups at rest. Seed regions are indicated with a circle on their respective activation maps above the connectivity maps, which reflect the p-values derived from an ANOVA. Colored seed labels represent the effect from which the seed was defined; green: Correct vs Fix, red: Error vs Fix. Right dlPFC was more strongly coupled with right ITG in controls, whereas left vmPFC was more strongly coupled with bilateral lOFC in patients. In controls, right SMG showed stronger coupling with right MTG. Controls also showed enhanced coupling within left postcentral gyrus, whereas patients showed increased coupling between this region and left insula. Colorbar denotes the −log(p) value and all the effects are shown at p<0.001 for illustration purposes.

Figure 4

Differences in functional connectivity between the groups during the task. Seed regions are indicated on their respective activation maps above the connectivity maps, which reflect the p-values derived from an ANOVA based on the average of three task runs in each subject. Colored seed labels represent the effect from which the seed was defined; red: Error vs Fix. The left thalamus showed enhanced coupling with dmPFC and left IPL in controls, whereas its connectivity to left PHG and left ROp was enhanced in patients. Functional connectivity between vmPFC and right PHG was enhanced in controls. Schizophrenia patients also showed increased coupling between middle temporal regions. Colorbar denotes the −log(p) value and all the effects are shown at p<0.001 for illustration purpose.