Diffusion Imaging Data Preprocessing and FA Analysis.

Diffusion MRI data were obtained from the PING Study database. Acquisition protocols for a high-resolution, T1-weighted scan and diffusion-weighted scans were standardized across sites dependent on the make of scanner, with most parameters constant across all locations (SI Methods). Image preprocessing and analysis were performed with a customized processing pipeline using Analysis of Functional NeuroImages (47) and FMRIB Software Library software packages (48). Images were corrected for both susceptibility-induced and eddy current distortions (49). Participant head movement during image acquisition was calculated, and realignment was performed across gradient direction slices. Gradient vector directions were rotated based on the motion correction. Gradient slices that were found to have head displacement greater than one-half of a voxel (1.25 mm) were excluded from the diffusion directions used for additional analyses, because data for that gradient direction were likely inaccurate because of movement. If more than one-half of the gradient slices in a participant’s data exceeded the movement threshold of 1.25 mm, the participant was excluded from additional analysis.

We examined structural connectivity for an a priori tract of interest, the UF, based on its identification as a major white matter tract connecting the prefrontal cortex and amygdala (22) and our prior evidence of phenotypic differences across mice and humans in frontoamygdala connectivity (14). Probabilistic tractography was used to determine UF masks on a participant by participant basis. Diffusion data were modeled using a crossing fiber technique described previously (Bayesian estimation of diffusion parameters obtained using sampling techniques) (50). A two-fiber model was created to perform probabilistic tractography and FA analysis. To determine the location of the UF in each participant, a mask in standard Montreal Neurological Institute (MNI) space was created to use as a seed region for tractography. The seed was placed at the site where the UF is known to ascend from the temporal lobe and loop anteriorly into the frontal lobe (Fig. 2A). An exclusionary mask was also placed posteriorly to the seed region to prevent detection of any tracts traveling posteriorly from the seed.

Participant FA maps were transformed into MNI space using a standard FA map, and probabilistic tractography was performed using the seed described. This technique resulted in individualized probabilistic maps, where the highly connected voxels showed a clear UF-shaped pattern that was easily isolated with a single threshold (4,000) held constant for all participants (Fig. 2A). The resulting probabilistic UF masks (both hemispheres) for each participant were inspected visually to ensure a trajectory consistent with the known shape of this major white matter tract (51). Each participant’s FA map was then masked using individualized UF masks. The FA values of included voxels were averaged, resulting in an average UF FA value for each participant. To test the specificity for results of analyses of the UF, analyses were also performed on the corticospinal tract, which served as a control tract (SI Methods and Fig. S3).