Mechanisms of Working Memory Impairment in Schizophrenia

Abstract

Background: The neural correlates of working memory (WM) impairment in schizophrenia remain a key puzzle in understanding the cognitive deficits and dysfunction of dorsolateral prefrontal cortex observed in this disorder. We sought to determine whether patients with schizophrenia exhibit an alteration in the inverted-U relationship between WM load and activation that we recently observed in healthy individuals and whether this could account for WM deficits in this population.

Methods: Medicated (n = 30) and unmedicated (n = 21) patients with schizophrenia and healthy control subjects (n = 45) performed the self-ordered WM task during functional magnetic resonance imaging. We identified regions exhibiting an altered fit to an inverted-U relationship between WM load and activation that were also predictive of WM performance.

Results: A blunted inverted-U response was observed in left dorsolateral prefrontal cortex in patients and was associated with behavioral deficits in WM capacity. In addition, suppression of medial prefrontal cortex during WM was reduced in patients and was associated with poorer WM capacity in patients. Finally, activation of visual cortex in the cuneus was elevated in patients and associated with improved WM capacity. Together, these findings explained 55% of the interindividual variance in WM capacity when combined with diagnostic and medication status, which alone accounted for only 22% of the variance in WM capacity.

Conclusions: These findings identify a novel biomarker and putative mechanism of WM deficits in patients with schizophrenia, a reduction or flattening of the inverted-U relationship between activation and WM load observed in healthy individuals in left dorsolateral prefrontal cortex.

Keywords: Cognitive impairment; Functional magnetic resonance imaging; Inverted-U; Schizophrenia; Short-term memory; Working memory.

Figure 1. Performance on the Self-ordered Working Memory Task

A) Accuracy, B) reaction time, and C) WM capacity data for participants in all three groups over all eight steps of the task. The dotted line in A) shows the level of accuracy expected by chance at each step.

Figure 2. Within-group activation and inverted-U fits during working memory

A) Regions showing significant activation (hot color spectrum) or deactivation (cool colors) to the self-ordered working memory task, as compared to the perceptual and motor control task. B) Regions in the current study cohort that show a significant positive fit to the inverted-U pattern of activation identified in our previous report in an independent sample of healthy individuals.

Figure 3. Group differences in inverted-U activation in dorsolateral prefrontal cortex, and associations with working memory capacity

A) Top: Region showing a significant difference between patients and controls in inverted-U fit within the dorsolateral prefrontal cortex region-of-interest. Bottom: Line plot showing activation at each step of the task in each of the three groups, within the region above. B) Regions showing a significant relationship between inverted-U fit and working memory capacity within the dorsolateral prefrontal cortex region-of-interest. Scatter plots show the average inverted-U fit in significant voxels for each participant, plotted against working memory capacity. Shaded regions on brain surfaces show the spatial extent of the dorsolateral prefrontal cortex region-of-interest.

Figure 4. Brain regions showing group differences and an association with working memory for either inverted-U fit or task activation

A) Regions in a whole-brain analysis showing both a significant difference between patients and controls and an association with working memory capacity in at least one group for the inverted-U fit. B) Regions in a whole-brain analysis showing both a significant difference between patients and controls and an association with working memory capacity in at least one group for activation to the self-ordered working memory task. Scatter plots in both A) and B) show the relationship between the circled region and working memory capacity, after adjusting working memory capacity for other predictors in the full model described in the main text. C) Working memory capacity regressions for a simple model including only diagnostic and medication grouping variables (left) and for a full model determined with step-forward model selection (right), including the four circled regions identified in panels A) and B).