Fig. 2. Cortical integrity trajectory model.

This simplified scheme illustrates structural gray matter changes in relation to the occurrence of manic episodes in bipolar disorder type 1. This model is based on results of the reviewed longitudinal studies depicting changes in prefrontal cortical integrity, the area most consistently reported, as representative example. Structural integrity is defined by the various structural brain imaging outcomes investigated in these studies (e.g., cortical thickness). Three events in time (A, B, C) between baseline and follow-up scans are indicated, at which a manic episode may or may not have occurred. Healthy control trajectory is shown in green, patient trajectories in blue. Patient average trajectory (gray) is based on general longitudinal findings showing no case-control differences with respect to change rates. Different shades of blue show example trajectories for patients who experienced none, one, two, or three manic episodes (ME) between imaging time points. Arbitrary units are used to express approximate trends. Additional notes: The illustration assumes that patients and controls are age matched at baseline. Although age-related slopes are not necessarily linear and may depend on age and follow-up period, linear slopes were illustrated for simplicity. Further, the average trajectory (gray arrow; same slope as controls) could potentially result from counterbalancing sub-group trajectories, where one group declines faster than controls and one show increased gray matter. This could potentially be the case if some patients experienced mania shortly before baseline imaging time point.