Conventional fMRI Analysis

We examined the effect of group (patients with BD, MDD relatives, healthy relatives and unrelated healthy controls) on BOLD signal using a standard general linear modelling (GLM) in SPM8 separately for each memory load condition (1-, 2-, 3- back) against the 0-back control. We examined each condition separately, instead of modelling activation changes with increasing load. This is because it has long been known that cortical loci, particularly in prefrontal regions, show non-linear changes in activation with increasing memory load (Callicott et al., 1999) which could increase voxel level variability. Suprathreshold clusters were identified using family wise error (FWE) voxel-wise correction of p<0.05. Stereotactic coordinates were converted from MNI spatial array to that of Talairach and Tournoux (www.mrc-cbu.cam.ac.uk/Imaging/mnispace.html) and corresponding anatomical and Brodmann area (BA) labels were identified with The Talairach Daemon Client (www.talairach.org). Measures of brain activation (weighted parameter estimates) from each subject were extracted using the MarsBaR toolbox (marsbar.sourceforge.net) from regions of interest (ROIs) defined on the basis of the whole brain analysis as 5 mm radius spheres at peak height coordinates within each suprathreshold cluster. These measures were also used to examine the role of potentially confounding variables of age, IQ, age of onset, task performance and medication. Although we report uncorrected P values, due to the large number of correlations undertaken the level of significant inference was set at a conservative P vale of 0.005.