Changes in the brain structural connectome after a prospective randomized clinical trial of lithium and quetiapine treatment in youth with bipolar disorder

Abstract

The goals of the current study were to determine whether topological organization of brain structural networks is altered in youth with bipolar disorder, whether such alterations predict treatment outcomes, and whether they are normalized by treatment. Youth with bipolar disorder were randomized to double-blind treatment with quetiapine or lithium and assessed weekly. High-resolution MRI images were collected from children and adolescents with bipolar disorder who were experiencing a mixed or manic episode (n = 100) and healthy youth (n = 63). Brain networks were constructed based on the similarity of morphological features across regions and analyzed using graph theory approaches. We tested for pretreatment anatomical differences between bipolar and healthy youth and for changes in neuroanatomic network metrics following treatment in the youth with bipolar disorder. Youth with bipolar disorder showed significantly increased clustering coefficient (C_p) (p = 0.009) and characteristic path length (L_p) (p = 0.04) at baseline, and altered nodal centralities in insula, inferior frontal gyrus, and supplementary motor area. C_p, L_p, and nodal centrality of the insula exhibited normalization in patients following treatment. Changes in these neuroanatomic parameters were correlated with improvement in manic symptoms but did not differ between the two drug therapies. Baseline structural network matrices significantly differentiated medication responders and non-responders with 80% accuracy. These findings demonstrate that both global and nodal structural network features are altered in early course bipolar disorder, and that pretreatment alterations in neuroanatomic features predicted treatment outcome and were reduced by treatment. Similar connectome normalization with lithium and quetiapine suggests that the connectome changes are a downstream effect of both therapies that is related to their clinical efficacy.

Fig. 1. Graphs show differences in global topological properties between patients with bipolar disorder and health controls at different time points.

The clustering coefficient (C_p) (p = 0.009) and characteristic path length (L_p) (p = 0.04) were significantly different between the two groups at the baseline. Increased C_p was still significantly different (p = 0.045) after 1 week’s treatment. An asterisk designates network metrics with a significant difference (p < 0.05).

Fig. 2. Graphs show the regions with significantly altered nodal centralities of the brain structural connectome in patients with bipolar disorder when compared with health controls at different time points.

The nodes were mapped onto the cortical surfaces by using the BrainNet Viewer package (http://www.nitrc.org/projects/bnv). DCG median cingulate and paracingulate gyri; IFGoperc inferior frontal gyrus, opercular part; INS insula; PCL paracentral lobule; area; PHG parahippocampal gyrus; SMA supplementary motor area; SPG superior parietal gyrus. R right hemisphere; L left hemisphere.

Fig. 3. Network parameters that changed over the course of treatment in bipolar patients.

Significant group-by-time effects were observed in both global level in C_p and L_p (A and B) and regional level in nodal efficiency and degree of right insula (C and D). F values of each significant time by group interaction are provided.

Fig. 4. Graphs show correlations of change in network metrics with change in clinical symptom severity.

A, B show relations of network metrics to symptom severity at baseline. C–F show relations between change of clinical symptom severity and normalization of altered network metrics at week 6. Abbreviations: SMA = supplementary motor area.