Bioenergetics and abnormal functional connectivity in psychotic disorders

Abstract

Psychotic Disorders such as schizophrenia (SZ) and bipolar disorder (BD) are characterized by abnormal functional connectivity (FC) within neural networks such as the default mode network (DMN), as well as attenuated anticorrelation between DMN and task-positive networks (TPN). Bioenergetic processes are critical for synaptic connectivity and are also abnormal in psychotic disorders. We therefore examined the association between brain energy metabolism and FC in psychotic disorders. ³¹P magnetization transfer spectroscopy from medial prefrontal cortex (MPFC) and whole-brain fMRI data were collected from demographically matched groups of SZ, BD, and healthy control (HC) subjects. The creatine kinase (CK) reaction flux calculated from spectroscopy was used as an index of regional energy production rate. FC maps were generated with MPFC as the seed region. Compared to HC, SZ showed significantly lower CK flux, while both BD and SZ patients showed decreased anticorrelation between MPFC and TPN. CK flux was significantly correlated with FC between MPFC and other DMN nodes in HC. This positive correlation was reduced modestly in BD and strongly in SZ. CK flux was negatively correlated with the anticorrelation between MPFC and TPN in HC, but this relationship was not observed in BD or SZ. These results indicate that MPFC energy metabolism rates are associated with stronger FC within networks and stronger anticorrelation between networks in HC. However, this association is decreased in SZ and BD, where bioenergetic and FC abnormalities are evident. This pattern may suggest that impairment in energy production in psychotic disorders underlies the impaired neural connectivity.

Figure 1:

(A) Default mode network and the anticorrelated task-positive network in healthy controls (HC), indicated by cold and warm colors respectively. (B) Areas with decreased anti-correlation with medial prefrontal cortex (MPFC) in bipolar disorder (BD, n=39) compared to HC (n=29). (C) Areas with decreased anti-correlation with MPFC in schizophrenia (SZ, n=27) compared to HC (n=29). (D) Areas with decreased anti-correlation with MPFC in SZ (n=27) compared to BD (n=39). In all figures, threshold was set to FDR corrected p<0.05. In the plot of (B) to (D), the differences were indicated by the warm colors. Images are shown in radiological convention with left side of the brain displayed on the right side of the image.

Figure 2:

(A) Brain areas whose functional connectivity (FC) with medial prefrontal cortex (MPFC) is significantly correlated with CK Flux, in healthy controls (HC, n=29), bipolar disorder (BD, n=39), and schizophrenia (SZ, n=27). (B) Brain areas whose FC with MPFC is negatively correlated with CK Flux, in HC (n=29), BD (n=39), and SZ (n=27). Images are shown in radiological convention with left side of the brain displayed on the right side of the image.

Figure 3:

(A) Correlation of CK flux and the functional connectivity (FC) between medial prefrontal cortex (MPFC) and other default mode network (DMN) areas, in healthy controls (HC, n=29, bipolar disorder (BD, n=39), and schizophrenia (SZ, n=27). (B) Correlation of CK flux and the FC between MPFC and task-positive network (TPN) areas in HC (n=29), BD (n=39), and SZ (n=27).