Aberrant intrinsic functional connectivity within and between corticostriatal and temporal-parietal networks in adults and youth with bipolar disorder

Abstract

Background: Major questions remain regarding the dysfunctional neural circuitry underlying the pathophysiology of bipolar disorder (BD) in both youths and adults. In both age groups, studies implicate abnormal intrinsic functional connectivity among prefrontal, limbic and striatal areas.

Method: We collected resting-state functional magnetic resonance imaging (fMRI) data from youths and adults (ages 10-50 years) with BD (n = 39) and healthy volunteers (HV; n = 78). We identified brain regions with aberrant intrinsic functional connectivity in BD by first comparing voxel-wise mean global connectivity and then conducting correlation analyses. We used k-means clustering and multidimensional scaling to organize all detected regions into networks.

Results: Across the brain, we detected areas of dysconnectivity in both youths and adults with BD relative to HV. There were no significant age-group × diagnosis interactions. When organized by interregional connectivity, the areas of dysconnectivity in patients with BD comprised two networks: one of temporal and parietal areas involved in late stages of visual processing, and one of corticostriatal areas involved in attention, cognitive control and response generation.

Conclusions: These data suggest that two networks show abnormal intrinsic functional connectivity in BD. Regions in these networks have been implicated previously in BD. We observed similar dysconnectivity in youths and adults with BD. These findings provide guidance for refining models of network-based dysfunction in BD.

Trial registration: ClinicalTrials.gov NCT00006177 NCT00025935.

Keywords: Bipolar disorder; children; functional connectivity; imaging; resting state.

Conflict of interest statement

Declaration of Interest

C.Z. is listed as a coinventor on a patent for the use of ketamine and its metabolites in major depression. C.Z. has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. All other authors have no conflicts of interest or outside financial support to report.

Figures

Fig. 1.

Boxplots of mean raw global connectivity values for each brain locale. These values are not adjusted for scanner or motion. These raw data are consistent with the voxel-wise analysis in that they demonstrate a pairwise diagnostic group [bipolar disorder (BD) v. healthy volunteer (HV); F1,113’s > 13.8, p’s < 0.001] but not age group or age group × diagnostic group interaction effects (p’s > 0.05). Across age categories, groups differed in global connectivity by rank testing (Wilcoxin test p’s ⩽ 0.002). Images of the locales are at their center of mass (see main text). R, Right; IPL, inferior parietal cortex; PCC, posterior cingulate cortex; L, left; STG, superior temporal gyrus; PrG, precentral gyrus.

Fig. 2.

(a) Correlation matrices of pairwise brain locale connectivity as Fisher’s r to z transform (rz). Locales are organized in the same order as Table 2, with locale 1 at the bottom left. Dashed lines represent boundaries of networks identified in cluster analyses (b), network 1 = bottom left and network 2 = top right. (b) Locale interrelationships are best described by two networks. Locales are plotted in two-dimensions of Euclidean distance from one another. The dimensions were determined by multidimensional scaling (MDS) all locale to locale interrelationships into two dimensions. The overall pattern suggests two functional networks, best separated by the first dimension. A separate analysis via k-means clustering also suggests a two-network solution, with red markers for locales in network 1 and yellow markers in network 2. (c) Heat map of t-statistics (here, Cohen’s d≈t × 0.19) for bipolar disorder–healthy volunteer (BD–HV) contrast of the individual’s pairwise rz values controlling for age category (youth v. adult), motion index and scanner. Positive t-statistics, representing hyperconnectivity in BD, are more common amongst pairwise relationships in network 2 and between networks 1 and 2. The threshold for significance is ∣t∣ > 3.9 for p < 0.05, Bonferroni corrected for 300 pairwise t tests. df, Degrees of freedom.

Fig. 3.

(a) Montage of all locales defined by bipolar disorder v. healthy volunteer intrinsic functional connectivity (iFC) differences. Locales clustered into two distinct networks represented by red (network 1) and yellow (network 2). (b) Overlap between the two circuits and seven cortical iFC networks parcellated from 1000 people, reported by Yeo et al. (2011).