Working memory circuitry in schizophrenia shows widespread cortical inefficiency and compensation

Abstract

Background: Working memory studies in schizophrenia (SZ), using functional magnetic resonance imaging (fMRI) and univariate analyses, have led to observations of hypo- or hyperactivation of discrete cortical regions and subsequent interpretations (e.g. neural inefficiencies). We employed a data-driven, multivariate analysis to identify the patterns of brain-behavior relationships in SZ during working memory.

Methods: fMRI scans were collected from 13 SZ and 18 healthy control (HC) participants performing a modified Sternberg item recognition paradigm with three memory loads. We applied partial least squares analysis (PLS) to assess brain activation during the task both alone and with behavioral measures (accuracy and response time, RT) as covariates.

Results: While the HC primary pattern was not affected by increasing load demands, SZ participants showed an exaggerated change in the Blood Oxygenation Level Dependent (BOLD) signal from the low to moderate memory load conditions and subsequent decrease in the greatest memory load, in frontal, motor, parietal and subcortical areas. With behavioral covariates, the separate groups identified distinct brain-behavior relationships and circuits. Increased activation of the middle temporal gyrus was associated with greater accuracy and faster RT only in SZ.

Conclusions: The inverted U-shaped curves in the SZ BOLD signal in the same areas that show flat activation in the HC data indicate widespread neural inefficiency in working memory in SZ. While both groups performed the task with similar levels of accuracy, participants with schizophrenia show a compensatory network of different sub-regions of the prefrontal cortex, parietal lobule, and the temporal gyri in this working memory task.

Figure 1

Performance measures for schizophrenia (SZ) and healthy control (HC) participants. Accuracy decreased with increasing number of items to remember, or working memory (WM) load, in both groups (1a). Response time (RT) slowed with load (WM) in both groups, with the SZ group showing a greater effect (1b).

Figure 2

Brain areas (2a) and brain score profiles for latent variables 1 (LV1) (2b) and LV3 (2c) in the Task Partial Least Squares (PLS) analysis. The areas indicated in Figure 2a are the areas which show the profile of Figure 2b. In both 2b and 2c, dashed lines indicate healthy controls (HC) and solid lines indicate schizophrenia (SZ) participants; closed circles indicate the encode conditions and open circles indicate the probe conditions. LV1 showed the distinction between areas specific to encode or probe conditions, and indicated the neural ineffiency in SZ through the hyperactivation in the moderate memory load conditions. See text for more description. See Table 2 and Supplemental Material 3 – 5 for full listings and further discussion of brain regions which were positively or negatively weighted on the various LV’s.

Figure 3

Correlation score profiles for latent variable 1 (LV1) (3a) and LV2 (3b) in the Behavior Partial Least Squares (PLS) analysis for accuracy. Dashed lines indicate healthy controls (HC) and solid lines indicate schizophrenia (SZ) participants; closed circles indicate the encode conditions and open circles indicate the probe conditions. LV1 showed a strong positive correlation between accuracy of working memory loads 1 and 5 in SZ group and the activated areas (namely the middle temporal gyrus, BA 21), while no such strong correlation was observed in the HC group (3a); in LV2, accuracy in the two groups depended heavily on different brain regions for the higher loads, suggesting the possible involvement of different circuits for each group (3b).

Figure 4

Correlation score profiles for latent variable 1 (LV1) (4a – left, HC data; right, SZ data) and LV3 (4b) in the Behavior Partial Least Squares (PLS) analysis for response time (RT). Dashed lines indicate healthy controls (HC) and solid lines indicate schizophrenia (SZ) participants; closed circles indicate the encode conditions and open circles indicate the probe conditions. A strong positive correlation with RT existed across all working memory loads in the SZ group in LV1 (4a – right), while no reliable correlation was observed in the HC group (4a – left). LV3 showed that RT was dependent on different circuits in the two groups, especially for the greater loads (4b).