Detecting the Inverted-U in fMRI Studies of Schizophrenia: A Comparison of Three Analysis Methods.

OBJECTIVE: Cognitive tasks are used to probe neuronal activity during functional magnetic resonance imaging (fMRI) to detect signs of aberrant cognitive functioning in patients diagnosed with schizophrenia (SZ). However, nonlinear (inverted-U-shaped) associations between neuronal activity and task difficulty can lead to misinterpretation of group differences between patients and healthy comparison subjects (HCs). In this paper, we evaluated a novel method for correcting these misinterpretations based on conditional performance analysis. METHOD: Participants included 25 HCs and 27 SZs who performed a working memory (WM) task (N-back) with 5 load conditions while undergoing fMRI. Neuronal activity was regressed onto: 1) task load (i.e., parametric task levels), 2) marginal task performance (i.e., performance averaged over all load conditions), or 3) conditional task performance (i.e., performance within each load condition). RESULTS: In most regions of interest, conditional performance analysis uniquely revealed inverted-U-shaped neuronal activity in both SZs and HCs. After accounting for conditional performance differences between groups, we observed few difference in both the pattern and level of neuronal activity between SZs and HCs within regions that are classically associated with WM functioning (e.g., posterior dorsolateral prefrontal and parietal association cortices). However, SZs did show aberrant activity within the anterior dorsolateral prefrontal cortex. CONCLUSIONS: Interpretations of differences in neuronal activity between groups, and of associations between neuronal activity and performance, should be considered within the context of task performance. Whether conditional performance-based differences reflect compensation, dedifferentiation, or other processes is not a question that is easily resolved by examining activation and performance data alone.