Enhanced temporal variability of amygdala-frontal functional connectivity in patients with schizophrenia

Abstract

Background: The "dysconnectivity hypothesis" was proposed 20 years ago. It characterized schizophrenia as a disorder with dysfunctional connectivity across a large range of distributed brain areas. Resting-state functional magnetic resonance imaging (rsfMRI) data have supported this theory. Previous studies revealed that the amygdala might be responsible for the emotion regulation-related symptoms of schizophrenia. However, conventional methods oversimplified brain activities by assuming that it remained static throughout the entire scan duration, which may explain why inconsistent results have been reported for the same brain region.

Methods: An emerging technique is sliding time window analysis, which is used to describe functional connectivity based on the temporal variability of regions of interest (e.g., amygdala) in patients with schizophrenia. Conventional analysis of the static functional connectivity between the amygdala and whole brain was also conducted.

Results: Static functional connectivity between the amygdala and orbitofrontal region was impaired in patients with schizophrenia. The variability of connectivity between the amygdala and medial prefrontal cortex was enhanced (i.e., greater dynamics) in patients with schizophrenia. A negative relationship was found between the variability of connectivity and information processing efficiency. A positive correlation was found between the variability of connectivity and symptom severity.

Conclusion: The findings suggest that schizophrenia was related to abnormal patterns of fluctuating communication among brain areas that are involved in emotion regulations. Unveiling the temporal properties of functional connectivity could disentangle the inconsistent results of previous functional connectivity studies.

Keywords: Amygdala; Dynamic functional connectivity; Schizophrenia; Sliding-window correlation analysis; Temporal variability.

Fig. 1

(A) Regions of interests (ROIs): left and right amygdala. (B) Compared with the healthy control (HC) group, the schizophrenia (SZ) group exhibited a decrease in functional connectivity between the amygdala and regions of the orbitofrontal cortex. (C) Compared with the HC group, the SZ group exhibited greater temporal variability of functional connectivity between the left amygdala and medial prefrontal cortex.

Fig. 2

To illustrate time window-by-window patterns of functional connectivity, the figure shows amygdala-medial prefrontal cortex (mPFC) functional connectivity values (Fisher's z-transformed Pearson's correlations) for each of the 19 sliding time windows. And the data represented by orange line is from one healthy subject, and the data represented by orange line is from one patient with schizophrenia. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Relationships between temporal variability of the amygdala-medial prefrontal cortex (mPFC) functional connectivity and clinical severity and cognitive performance. (A) Negative correlation between temporal traits of amygdala-mPFC functional connectivity and information processing speed. (B) Positive correlation between temporal traits of amygdala-mPFC functional connectivity and total symptom severity.