Impairment of working memory maintenance and response in schizophrenia: functional magnetic resonance imaging evidence

Abstract

Background: Comparing prefrontal cortical activity during particular phases of working memory in healthy subjects and individuals diagnosed with schizophrenia might help to define the phase-specific deficits in cortical function that contribute to cognitive impairments associated with schizophrenia. This study featured a spatial working memory task, similar to that used in nonhuman primates, that was designed to facilitate separating brain activation into encoding, maintenance, and response phases.

Methods: Fourteen patients with schizophrenia (4 medication-free) and 12 healthy comparison participants completed functional magnetic resonance imaging while performing a spatial working memory task with two levels of memory load.

Results: Task accuracy was similar in patients and healthy participants. However, patients showed reductions in brain activation during maintenance and response phases but not during the encoding phase. The reduced prefrontal activity during the maintenance phase of working memory was attributed to a greater rate of decay of prefrontal activity over time in patients. Cortical deficits in patients did not appear to be related to antipsychotic treatment. In patients and in healthy subjects, the time-dependent reduction in prefrontal activity during working memory maintenance correlated with poorer performance on the memory task.

Conclusions: Overall, these data highlight that basic research insights into the distinct neurobiologies of the maintenance and response phases of working memory are of potential importance for understanding the neurobiology of cognitive impairment in schizophrenia and advancing its treatment.

Figures

Figure 1

Timing of trial events for the 4-target task. Colored rectangles show sampling periods for the encoding peak (blue, 6–21s after trial start), the maintenance trough (green, 13.5–28.5s), the response peak (yellow, 21–36s) and the baseline (orange, 0–1.5 and 37.5–39). The peaks were defined as the image with the highest percent signal change from baseline during the sampling period and the trough was defined as the image with the lowest percent signal change from baseline during the sampling period. Note that, because of the hemodynamic delay, sampling periods lag behind trial events. ITI = intertrial interval.

Figure 2

Regions of interest used in analysis. R=right. SMFG = superior middle frontal gyrus, MFG = middle frontal gyrus, IFG = inferior frontal gyrus, VIFG = ventral inferior frontal gyrus.

Figure 3

Timecourses of all regions of interest used in analysis by group and task. Blue represents the stimulus encoding period when participants are viewing targets and yellow the probe period. Timecourses are normalized by subtracting the mean baseline from each timepoint shown. SMFG = superior middle frontal gyrus, MFG = middle frontal gyrus, IFG = inferior frontal gyrus, VIFG = ventral inferior frontal gyrus. SZS = patients with schizophrenia. HCS = healthy comparison subjects.

Figure 4

Correlation between encoding peak and maintenance trough in HCS (top) and in SZS (bottom) averaging over the 2-target and 4-target tasks. SMFG = superior middle frontal gyrus, MFG = middle frontal gyrus, IFG = inferior frontal gyrus, VIFG = ventral inferior frontal gyrus. SZS = patients with schizophrenia. HCS = healthy comparison subjects.

Figure 5

Correlation between response peak and maintenance trough in HCS (left) and SZS (right) during the 2-target (top) and 4-target tasks (bottom). SMFG = superior middle frontal gyrus, MFG = middle frontal gyrus, IFG = inferior frontal gyrus, VIFG = ventral inferior frontal gyrus. SZS = patients with schizophrenia. HCS = healthy comparison subjects.